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

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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Pilot Study on Frailty and Functionality on Routine Clinical Assessment in Allogeneichematopoietic Cell Transplantation to Predict Outcomes

Blood ◽

10.1182/blood-2019-126071 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 380-380 ◽

Cited By ~ 1

Author(s):

Maria Queralt Salas ◽

Eshetu G Atenafu ◽

Ora Bascom ◽

Leeann Wilson ◽

Arjun Law ◽

...

Keyword(s):

Stem Cell ◽

Pilot Study ◽

Stem Cell Transplantation ◽

Grip Strength ◽

Cell Transplantation ◽

Waiting Time ◽

Acute Gvhd ◽

Number Of Patients ◽

And Function

Introduction: Frailty can adversely affect the outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT) but is difficult to measure in busy transplant clinics. The limited published studies have used dedicated trained persons and comprehensive geriatric assessment (GA) tools, which are time consuming (Muffly LS, Haematologica 2014; Holmes HM, J Geriatr Oncol 2014; Rodrigues M, J Geriatr Oncol 2019). The difficulty in application of GA tools by transplant clinicians, residents and nurses in their clinics has resulted in low adoption rates in routine practice. At our center we adopted selected tests for frailty and function which could be conducted during pre-transplant consultation in a busy clinic, without extra waiting time for patients, and using existing staff. The Timed up and Go test (TUGT) was adopted as it could be done in any closed clinic room, without need for a corridor. Thus it was considered safer than a gait speed test and was even applicable to patients in "isolation". We aim to share a preliminary analysis of the applicability and correlation between our selected frailty assessment with transplant outcomes and complications. Methods: Patients referred for transplant underwent the following assessments conducted by different providers. All ages were included. Relevant tests and source of data are as follows: Frailty and function by clinician evaluating (a) Clinical Frailty scale (CFS) with 9 points based on clinical judgement (Rockwood 2005) (b) Lawton's Instrumental activities of daily living (IADL). Objective physical performance by nursing BMT coordinator using (a) TUGT and (b) Grip strength using hydraulic "Jamar" hand dynamometer conducted in clinic room at time of documentation. Self assessment by patient completing (a) Self-rated health (SRH) question and (b) a question on falls. Blood tests (a) CRP (b) Albumin. The present study is a single center prospective observational study. Patients who did not proceed to transplant were excluded. Ninety-six consecutive adult allo-HSCT patients were eligible for the present analysis, updated on July 2019. The parameters were individually correlated with overall survival (OS), non-relapse mortality (NRM), cumulative incidence (cum.Inc) of acute GVHD, median time of transplant hospitalization and readmissions. Multivariate analysis was not performed in this pilot study due to limited number of patients and low frequency of adverse events. Results: Baseline characteristics and main post-transplant information are noted in Table 1. Median follow up of cohort was 5 months. Table 2 shows the main outcomes (with normal values). For the entire cohort the median OS at 6 months was 73.9% (range 61.7-82.8), NRM at day+100 was 8.7% (range 2.6-14.7), Cum.Inc of Acute GVHD 41.1% (range 30.1-52.1), Cum.Inc gr II-IV acute GVHD was 25.7% (range 15.6-35.9). Relapse occurred in 8 cases (8.3%) and deaths in 23 (23.9%). A TUGT of more than 10 seconds and raised CRP predicted poor OS (p<0.05). Abnormal TUGT, SRH question score of <A (excellent), lower albumin levels and raised CRP levels correlated with high NRM (p<0.05). A Clinical Frailty Score of more than 2, limitations of 1 or more IADLs, Grip strength below normal for age and sex, TUGT >10 seconds, SRH question <A, and lower albumin level were significant predictors for a longer median duration of transplant hospitalization. No frailty or functionality parameter correlated significantly with the Cum.Inc of any grade of acute GVHD, grade II-IV acute GVHD or the risk of rehospitalization after alloHSCT. Conclusions: Our pilot study shows that with selected brief tools, frailty and functionality can be assessed as part of routine clinical practice in allogeneic-stem cell transplantation in all age groups without extra waiting time for patients or additional human resources. TUGT is a useful prognostic tool which can be conducted in a clinic room and correlates with OS, NRM, and duration of hospitalization. Larger number of patients and longer follow-up will help to evaluate the different assessment modalities as prognostic tools in allo-HSCT and their wider applicability. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria.

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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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Improved Immune Reconstitution Following Pre-Emptive CD8-Depleted Donor Lymphocyte Infusions (DLIs) after Haploidentical Stem Cell Transplantation (SCT) Using a Reduced-Intensity Conditioning (RIC) Regimen.

Blood ◽

10.1182/blood.v106.11.2908.2908 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2908-2908

Author(s):

Paolo Corradini ◽

Anna Raganato ◽

Matteo Carrabba ◽

Lorenza Gandola ◽

Claudia Lombardo ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Total Dose ◽

Cell Transplantation ◽

Immune Reconstitution ◽

Hematological Malignancies ◽

Acute Gvhd ◽

Immune Recovery ◽

Grade Ii ◽

The Impact

Abstract Allogeneic stem cell transplantation (SCT) from an haploidentical family donor has been reported as a viable option in acute leukemias when matched donors are unavailable. However, the extensive T-cell depletion (TCD), required to prevent graft-versus-host disease (GVHD), is associated to delayed immune recovery and high transplant-related mortality. In an ongoing phase I–II trial for patients (pts) with advanced hematological malignancies, we combined a RIC regimen, including thiotepa (10 mg/kg), fludarabine (120 mg/ms), cyclophosphamide (60 mg/kg) and TBI (2 Gy), with pre-emptive administration of CD8-depleted DLIs (starting from 1x104 up to 1x105 cells/kg). Ex-vivo and in-vivo TCD were carried out by CD34+ cell selection using the CliniMACS device and alemtuzumab (30 mg day −2), respectively. The aim of the study was to investigate in a dose finding study the safety and the impact on immune-reconstitution of CD8-depleted DLIs. Six-teen pts with hematological malignancies (n=14 NHL/HD, n=1 ALL, n=1 AML) were included, median age was 35 years (range, 15–65), 10 (63%) were chemorefractory, and 68% and 75% had failed a previous auto or at least 3 CT lines, respectively. Pts received a median of 10.6 x106/Kg CD34+ and 1x104/kg CD3+. All pts engrafted with full donor chimerism from day +30. At a median follow-up of 9 months, 12 pts were alive and 4 died (n=1 infection, n=3 disease). The estimated OS at 2 years was 58%; 7 of 16 (44%) relapsed at median time of 100 days after SCT. CD8-depletion of 14 donor lymphocyte aphereses was performed with a new depletion protocol (Clinimacs CD8-Microbeads) that reduces the content of CD8+ cells by at least 3 logs. The median CD3+, CD4+, CD56+/CD3+, CD20+ cell recovery were 62% (range, 35–91%), 88% (63–128%), 51% (8–78%), 76% (33–128%), respectively. Before DLIs, only 1 of 16 pts (6%) developed de novo acute GVHD (grade II). A total of 22 CD8-depleted DLIs were administered to 9 of 16 pts without any engraftment problem. The first cohort of pts (n=5) received a total dose of 3–6x104/kg CD8depleted DLIs starting at day +45 divided in 3 monthly infusions: none of them developed aGVHD. Given no toxicity, we escalated doses and the second cohort (n=4) received a total dose of 10–25x104/kg CD8-depleted DLIs divided in 3 monthly infusions: 3 pts had acute GVHD (grade II). Overall, the incidence of acute GVHD was higher (75% vs 0%, P<0.04) in pts receving larger numbers of donor cells. Interestingly, the median values of CD4+/ul and CD8+/ul were 98 (range, 8–612) and 150 (range, 15–988) at 4 months; 247 (range, 55–333) and 235 (range, 3–1000) at 5 months after SCT. The median value of CD19+/ul cells were 134 (range, 0–292) and 160 (range, 0–256) at 4 and 5 months, respectively. NK cells remained between the value of 394/ul and 569/ul in the first 6 months after SCT. Our results suggest that: (1) haploidentical SCT with RIC regimen is feasible with a high rate of engraftment and a low acute GVHD incidence; (2) pre-emptive CD8-depleted DLIs are feasible without GVHD until the total dose of 6 x104/kg; 3) higher doses can induce acute GVHD, but no grade III–IV was observed; 4) despite the limited number of pts, we observed a faster immune recovery and a relatively low mortality rate for infections.

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

Blood ◽

10.1182/blood.v118.21.4267.4267 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4267-4267

Author(s):

Ana Garrido ◽

Miguel Ortín ◽

Rodrigo Martino ◽

Josep Nomdedeu ◽

Ana Aventin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Cell Transplantation ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Complete Response ◽

Cell Transplant ◽

Safe Procedure

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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The Impact of Age in Allogeneic Stem Cell Transplantation with Thiotepa Busulfan and Fludarabine (TBF) for Myelofibrosis : A Retrospective Analysis

Blood ◽

10.1182/blood-2021-145711 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4858-4858

Author(s):

Federica SORA ◽

Patrizia Chiusolo ◽

Sabrina Giammarco ◽

Idanna Innocenti ◽

Francesco Autore ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Total Dose ◽

Cell Transplantation ◽

Older Patients ◽

Research Funding ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

The Impact

Abstract Allogeneic hematopoietic stem-cell transplantation (HSCT) currently remains the only curative therapy for intermediate or high risk disease.myelofibrosis (MF). We are reporting 56 patients (pts) who underwent an allogeneic HSCT in our Centre between 2016 and 2020, and assessed factors predictive of outcome. The median age was 59 years (36-72). Most patients (72%) were JAK2+ and had int2-high DIPSS (92%). The conditioning regimen consisted of thiotepa, busulfan , fludarabine (TBF). All pts received thiotepa 10 mg/kg and fludarabine 150 mg/m^2. The dose of busulfan was adjusted considering the age and the comorbidity score. One pt received 3 days of busulfan (total dose 9.6 mg/kg); 47 received 2 days (total dose 6.4 mg/kg) and 8 received one day of busulfan iv (3.2 mg/kg). Donor was an identical sibling in 13 pt, haploidentical in 18, matched unrelated donor (UD) in 18 and a mismatchedUD in 7. Thus we had 31 HLA matched and 25 HLA mismatched grafts. Fortytwo patients received post-transplant cyclophosphamide (PTCy)-based GVHD (Graft versus host disease ) prophylaxis with cyclosporine and mycophenolate mofetil , and 14 patients received a standard GvHD prophylaxis (CSA+MTX+ATG). The 2 year survival (OS) was 73 % and disease free survival (DFS) was 66 % and the cumulative incidence (CI) of TRM was 23% and of relapse 11%. The incidence of acute GvHD grade II-IV was 22% in HLA matched and 50% in HLA mismatched pts (p=0.022), grade III-IV was 6% and 25% respectively (p=0.042) . The incidence of moderate-severe chronic GvHD was 25% in HLA matched and 36% in HLA mismatched grafts (p=0.36). HLA had a major impact on survival : 85% vs 49% survival for matched vs mismatched patients (p=0.01). Patients age >60 years had a major impact on outcome, with a 2 year survival of 51% vs 88% in patients over (n=24) or under 60 years of age (n=32) (p=0.007; the DFS was 46 % and 80% respectively and the CI of TRM was 42% vs 9% (p=0.003). As to the total dose of busulfan, we found 26% TRM in patients receiving busulfan for 2 days (total doe 6.4 mg/kg) (n=47) and 0% in older patients receiving 1 day only (total dose 3.2 mg/kg) (n=8) ; relapse rate was 10% and 20% respectively. In multivariate cox analysis including age, spleen size ,DIPSS score, number of transfusion received and donor type, only HLA matching influenced the incidence of acute GvHD; transfusion burden and age plays a role in NRM and OS; DIPSS predicts relapse . In conclusion: older patients with MF have a high NRM and need to be prepared with a milder conditioning regimen. Disclosures Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.

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International Consensus Criteria for Tyrosine Kinase Inhibitor Response and Outcome of Allogeneic Stem Cell Transplantation for CML

Blood ◽

10.1182/blood.v120.21.1997.1997 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1997-1997

Author(s):

Sairah Ahmed ◽

Rima M Saliba ◽

Marcos De Lima ◽

Tobi DeAnn Fisher ◽

Gabriela Rondon ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Tyrosine Kinase ◽

Disease Progression ◽

Cell Transplantation ◽

Chronic Phase ◽

Disease Status ◽

International Consensus ◽

Conditioning Treatment

Abstract Abstract 1997 Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with chronic myeloid leukemia (CML), and is reserved for those who do not respond optimally to tyrosine kinase inhibitors (TKI). Baccarani et al summarized international consensus criteria (ICC) for response to imatinib in first chronic phase (CP) based on time to response; these criteria are used to select alternative therapies including second generation TKIs or HSCT for less than optimal responses. (Baccarani M, et al.J Clin Oncol. 2009; 27:6041–6051). Patients in blast crisis (BC) or accelerated phase (AP) proceed for HSCT if eligible, regardless of optimal response. The prognostic influence of ICC stratification prior to transplant is unknown. We hypothesized the ICC would influence progression after HSCT in patients with CML; in this study we report the impact of this score on transplant outcomes. Patients and Methods We performed a retrospective review of patients with CML who underwent a reduced intensity conditioning treatment with busulfan/fludarabine/ATG ± imatinib followed by HSCT. From 1/2000 to 5/2012, 104 patients underwent a matched unrelated or related allogeneic HSCT at the M.D. Anderson Cancer Center. The ICC was applied to patients prior to transplant to denote optimal, suboptimal, or failure of response to a TKI. Demographic and disease-related data were collected, as well as transplant-related covariates. Outcome of interest was progression free survival (PFS) and overall survival (OS), which was estimated using the Kaplan-Meier method. Results Patient characteristics are summarized in Table 1, and analysis in Table 2. 36/104 patients received a conditioning treatment containing imatinib and PFS was not statistically different. With median follow up of 36 months (1–126), 62 patients are alive and 30 patients have progressed. Of the 42 deaths, 27(64%) were primarily attributed to leukemia relapse, 3 (9%) infection, 6(17%) graft versus host disease and 6(10%) of other causes. OS was 50% (38–61%) at last follow up and 55% (44–65%) at 36 months. By multivariate analysis, factors predicting progression were: disease status CP1 vs >CP1 (p=0.001) and failure vs optimal/suboptimal response to TKI as defined by ICC (p=0.02). Optimal or suboptimal response defined by ICC was not an independent predictor of the rate of disease progression, OS, or PFS. 77% of patients in the most advanced disease group (AP2/BC/≥CP3) failed to respond to a TKI compared with 44% of patients in CP1 and intermediate group (CP2/AP1/CE), (p=0.006). Age >50 yrs was associated with a trend for higher disease progression, and lower OS and PFS but did not reach significance. There was no impact of ICC stratification in first chronic phase patients; only one patient died or progressed despite 48% identified as failure based on ICC score. Conclusion In this single center study with long follow up, we demonstrated ICC score is strongly correlated with disease status at transplant. The latter factor remains the most significant predictor of outcomes. Patients transplanted in first chronic phase have a low rate of progression with allogeneic hematopoietic transplantation regardless of response to TKI therapy based upon ICC score. Disclosures: No relevant conflicts of interest to declare.

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Risk Factors and Outcomes for Patients With Follicular Lymphoma Who Had Histologic Transformation After Response to First-Line Immunochemotherapy in the PRIMA Trial

Journal of Clinical Oncology ◽

10.1200/jco.2015.65.7163 ◽

2016 ◽

Vol 34 (22) ◽

pp. 2575-2582 ◽

Cited By ~ 85

Author(s):

Clémentine Sarkozy ◽

Marek Trneny ◽

Luc Xerri ◽

Nick Wickham ◽

Pierre Feugier ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Follicular Lymphoma ◽

Disease Progression ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

International Prognostic Index

Purpose To study the outcome of histologic transformation (HT) in a large prospective cohort of patients with follicular lymphoma (FL) who previously responded to immunochemotherapy. Patients and Methods After a median 6-year follow-up of 1,018 randomly assigned patients from the PRIMA trial, disease progression was observed in 463 patients, 194 of whom had histologic documentation. Results Forty patients had histology consistent with HT, and 154 had untransformed FL (median time to recurrence, 9.6 v 22.8 months, respectively; P = .018). Thirty-seven percent of biopsies performed during the first year of follow-up showed HT corresponding to 58% of all HTs. Altered performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis were identified as HT risk factors. Response (complete v partial) to immunochemotherapy or rituximab maintenance had no impact on the risk of HT. After salvage treatment, patients with HT had less frequent complete response (50.3% v 67.4%; P = .03) and more disease progression (28.2% v 9.6%; P < .001) than patients without HT. Estimated overall survival for the patients with HT was poorer (median, 3.8 v 6.4 years; hazard ratio, 3.9; 95% CI, 2.2 to 6.9). Autologous stem cell transplantation improved the outcomes of patients with HT (median overall survival, not reached v 1.7 years) but not of patients with persistent FL histology. Conclusion HT in patients with FL who previously responded to immunochemotherapy is an early event associated with a poor outcome that may deserve intensive salvage with autologous stem cell transplantation. These data emphasize the necessity for biopsy at the first recurrence of FL.

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

Cancers ◽

10.3390/cancers13112699 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2699

Author(s):

Panagiotis Tsirigotis ◽

Konstantinos Gkirkas ◽

Vassiliki Kitsiou ◽

Spiros Chondropoulos ◽

Theofilos Athanassiades ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Acute Leukemia ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Low Dose ◽

Acute Gvhd ◽

Donor Lymphocyte Infusion

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

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Allogeneic Stem Cell Transplantation (allo-SCT) for Chronic Lymphocytic Leukemia: a Long Term Analysis From the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).

Blood ◽

10.1182/blood.v114.22.201.201 ◽

2009 ◽

Vol 114 (22) ◽

pp. 201-201

Author(s):

Mohamad Mohty ◽

Jean-Paul Vernant ◽

Ibrahim Yakoub-Agha ◽

Didier Blaise ◽

Gérard Socié ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Chronic Lymphocytic Leukemia ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Acute Gvhd ◽

Disease Status ◽

Lymphocytic Leukemia

Abstract Abstract 201 Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with a heterogeneous natural history. While some patients never require treatment or can be managed effectively with conventional chemotherapy, others experience early disease progression and death. Allo-SCT is increasingly considered as a therapeutic option for younger patients with poor-risk CLL. This multicenter retrospective analysis assessed the long term outcome of 160 CLL patients who received allo-SCT between 1987 and 2005, and were reported to the SFGM-TC registry. This series included 127 males (79%) and 33 females (20.6%) with a median age at CLL diagnosis of 45.5 (range, 24.4–65.1) y. The median age at time of allo-SCT was 50.9 (range, 29.8–68.3) y. Before allo-SCT, 26 patients (16.3%) received previous stem cell transplantation in the course of their disease. Patients received either a standard myeloablative conditioning regimen (n=58; 38%; Cy-TBI in 90% of cases) or a so-called reduced-intensity conditioning. A matched-related donor was used in 142 cases (89%) and PBSCs were used as source of stem cells in 92 cases (57.5%). At time of allo-SCT, only 10 patients (6.3%) were in CR1, 17 in CR2 and CR3 (10.6%), 27 in first PR (16.9%) and 106 (66.2%) in more advanced phases, including 46 patients (28.8%) in progressive disease. With a median follow-up of 60 (range, 1.6–208) months for surviving patients, 96% of patients engrafted (ANC>500/μL) at a median of 18 (range, 1–41) days after allo-SCT. 71 patients (44.4%) experienced grade 2–4 acute GVHD, including 28 cases (17.5%) of grade 3–4 acute GVHD. 73 patients (56.2%) experienced some form of chronic GVHD. At time of last follow-up, 70 patients (43.8%) were still alive, of whom 24 (34%) were in continuous CR. Disease progression accounted for 24 deaths, while transplant-related causes (infections, n=23; GVHD, n=13; MOF, n=12; other causes, n=18) were observed in 66 cases, for a TRM rate of 41%. The KM estimates of disease-free survival (DFS) at 2, 5, and 10 years after allo-SCT were 44.3%, 39.6%, and 30.5%, respectively. Estimates of overall survival (OS) were 54.4%, 46.2%, and 35.8.1%, respectively. In a Cox multivariate analysis for OS (including demographic features, transplant and donor types, and disease status at time of allo-SCT), disease status at time of allo-SCT (CR or PR) was the most significant parameter associated with improved OS (RR=0.56; 95%CI, 0.36–0.89). We conclude that allo-SCT has the potential to induce long-term disease control and overall survival in patients with high risk or advanced CLL. Disclosures: No relevant conflicts of interest to declare.

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Fludarabine, Low Dose Busulfan and Antithymocyte Globulin (ATG) Compared to Fludarabine and Low Dose Total Body Irradiation (TBI) for Reduced-Intensity Conditioning (RIC) Prior to Allogeneic Stem Cell Transplantation (allo-SCT) In Patients with Lymphoid Malignancies.

Blood ◽

10.1182/blood.v116.21.3472.3472 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3472-3472

Author(s):

Florent Malard ◽

Eolia Brissot ◽

Patrice Chevallier ◽

Thierry Guillaume ◽

Jacques Delaunay ◽

...

Keyword(s):

Stem Cell ◽

Total Dose ◽

Relapse Rate ◽

Low Dose ◽

Chronic Gvhd ◽

Routine Practice ◽

Unrelated Donor ◽

Toxicity Profile ◽

Lymphoid Malignancies ◽

Grade 3

Abstract Abstract 3472 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 for lymphoid neoplasms. With this background, this retrospective analysis was performed to assess whether a RIC regimen including fludarabine (120 mg/m2), low dose busulfan (4 mg/Kg total dose administered orally over a single day) and ATG (Thymoglobuline®, 2.5 mg/Kg/d for 2 days; FB1A protocol, n=44), is a valid alternative to the classical RIC regimen including fludarabine (90 mg/m2) and TBI (2 Gy.) (FTBI, n=27) prior to allo-SCT. The cohort included 37 males (52%) and 34 females (48%) treated consecutively in a single centre, with a median age at time of allo-SCT of 53 (range, 15–66) y. Diagnoses included 39 NHL (55%), 17 Hodgkin lymphomas (24%), 12 CLL (17%) and 3 myeloma (4%). 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 43 (range, 3.7–85) months after allo-SCT, all patients, but one (from the FTBI group) engrafted. In the FB1A group, the acute grade 3–4 GVHD rate was 20.5% (n=9), the chronic GVHD rate was 32% (n=14), the relapse rate was 23% (n=10) and the TRM rate was 25% (n=11). In the FTBI group, the rate of grade 3–4 acute GVHD rate was 44% (n=12; P=0.03 in comparison to the FB1A group), the chronic GVHD rate was 52% (n=14; P=0.09), the relapse rate was 15% (n=4; P=NS) and the TRM rate was 37.0% (n=10; P=NS). At 2 years, overall survival was 66% (95%CI, 51–78%) in the FB1A group versus 55% (95%CI, 36–73%) in the FTBI group (P=NS). Disease-free survival (DFS) was also comparable between both groups (at 2 years, 59% in the FB1A group, vs. 48% in the FTBI group, P=NS). In a Cox multivariate analysis for OS or DFS, the type of RIC regimen was not significantly associated with outcome. In all, these results suggest that in patients with lymphoid malignancies, a RIC regimen including Fludarabine, ATG and low dose busulfan (4 mg/Kg total dose) is a valid alternative to the classical Fludarabine and low dose TBI-based RIC regimen with a favorable toxicity profile and efficient disease control. Disclosures: No relevant conflicts of interest to declare.

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