Reduced-intensity Conditioning Allogeneic Stem Cell Transplantation Research Articles

RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Final Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO - SFGM-TC French intergroup)

RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Final Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO - SFGM-TC French intergroup)

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Cytomegalovirus Status and the Outcome of T Cell–Replete Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

Cytomegalovirus (CMV) serostatus of donor and recipient are frequently used in algorithms of donor selection, whereas the impact of CMV reactivation on transplantation-related mortality, leukemia control, and overall survival (OS) remains controversial. Therefore, we retrospectively studied the impact of latent or active CMV infections on the outcome and occurrence of graft-versus-host disease (GVHD) after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (SCT) in 294 patients during the period from 2004 to 2010. CMV viral load was routinely monitored in plasma using a quantitative PCR. Preemptive antiviral therapy was initiated when the viral load in plasma exceeded a predefined threshold. In a proportional hazards model, a seropositive recipient was significantly associated with increased occurrence of acute GVHD. However the CMV serostatus of both recipient and donor and the presence of active CMV infection was not associated with the occurrence of relapses, chronic GVHD, or OS. We conclude that in the presence of viral load monitoring and preemptive treatment, latent or active CMV infection does not substantially affect the OS after T cell–replete RIC allogeneic SCT.

Allogeneic stem cell transplantation for patients with mantle cell lymphoma who failed autologous stem cell transplantation: a national survey of the SFGM-TC.

Poly-chemotherapy plus rituximab followed by autologous stem cell transplantation (auto-SCT) is standard care for untreated young patients with mantle cell lymphoma (MCL). Despite this intensive treatment, transplant patients remain highly susceptible to relapse over time. The French SFGM-TC performed a national survey on reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) for fit relapsed/refractory patients who failed after auto-SCT (n=106). Median times of relapse after auto-SCT, and from auto-SCT to RIC-allo-SCT were 28 months and 3.6 years, respectively. Sixty per cent of patients received at least three lines of treatment before RIC-allo-SCT. Conditioning regimens for RIC-allo-SCT were heterogeneous. Twenty patients experienced grade III/IV aGvHD, extensive cGvHD was reported in 28 cases. Median follow-up after RIC-allo-SCT was 45 months. Median PFS after RIC-allo-SCT was 30.1 months and median overall survival was 62 months. Treatment-related mortality (TRM) at 1 year and 3 years were estimated at 28% and 32%, respectively. A total of 52 patients died; major causes of death were related to toxicity (n=34) and MCL (n=11). Patients in good response before RIC-allo-SCT experienced a better PFS and OS. Our work highlights the need for new RIC-allo-SCT MCL-tailored approaches to reduce TRM, and early and late relapse.

RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Intermediate Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO & SFGM-TC French intergroup)

Introduction Reduced intensity conditioning (RIC) allogeneic stem cell transplantation (ASCT) remains a valuable and potentially curative strategy in high-risk CLL. Post-ASCT relapse remains an important (30-40%) cause of failure, predicted by persisting positive minimal residual disease (MRD) at 12m post-ASCT. ASCT is also associated with a toxic mortality and with the burden of chronic graft versus host disease (cGVHD). We evaluated the efficacy and safety of a preemptive immunointervention (PrIm) based on serial MRD assessment in high-risk CLL. (NCT01849939)Methods Main inclusion criteria were (1) EBMT criteria for ASCT, (2) CLL in PR/CR, (3) mass ≤5cm, (4) age ≤70, (5) SORROR score ≤2 and (6) HLA donor (10/10). RIC regimen included fludarabine 120 mg/m2, IV busulfan 6.4 mg/kg, rabbit ATG 5mg/kg and CsA prophylaxy. Centralized 10-color flow cytometry blood MRD was assessed before and at M1, M2, M3, M4, M5, M6, M9 and M12 post-ASCT. MRD[-] was defined by blood detection <10e-4 at 2 consecutive time-points, confirmed (if possible) on bone marrow aspiration. PrIm algorithm, applied from D30 to M12, considered IWCCL response criteria, blood MRD and GVHD occurrence/severity. PrIm comprised tutored CsA early (≤4-5m), standard (6m) or late (7m) tapering and discontinuation (T&D). Early CsA T&D was followed in case of failure to achieve MRD[-] by 1-3 increasing DLI doses (1, 5 or 10x10e6 CD3/kg). Primary end point was the rate of MRD[-] at M12. Chimerism was assessed in parallel on full blood and on sorted CD3+ cells and was not a part of PrIm decision.Results As of 2015, August the 1st, the 43 planned inclusions have been done. Before their last line prior to ASCT, pts had: (a) presence of a del(17p) in 1st line (n=24) or in relapse (n=3), (b) absence of del(17p) but relapse ≤2y post fludarabine-based combination (n=14) or post-autologous transplantation (n=1). At time of transplantation, 11/43 (26%) had achieved CR, 28/43 (65%) had achieved PR, 2/43 (5%) had SD with 2 unknown status. Six patients had undetectable MRD (limit of detection: 5x10-6). For the 37 other patients, the median pre-ASCT MRD level was 2.35%(0.014 to 70%).The results of these 43 pts will be available in December 2015. This abstract describes the outcome of the 30 first consecutive pts including 26 pts evaluable [alive with ≥12m post-ASCT follow-up] and 4 pts non evaluable [death at M10 (n=1; sepsis) and at M8 (n=1 GVHD), EBV induced lymphoproliferation (n=1) and immediate graft rejection (n=1)], all included in the ITT analysis. In the 29 pts with full engraftment, the full blood chimerism at 3m and 12m was 99.1[62.1 ;99.8] and 99.5[59.4 ;99.9], and the T-cell specific chimerism was 99.2[5.2;99.8] and 99.6[21.1;99.8], with 30% and 25% >95% donor derived CD3+ cells respectively. MRD evolution followed different patterns (Table 1). At the M3 checkpoint, among evaluable patients, 10 were already MRD[-], and 16 were still MRD[+]. Then 10 pts became MRD[-] and 6 remained MRD[+]. This approach achieved 67% blood MRD[-] at M12 (ITT). When early CSA T&D had failed DLI done in 6 pts did not achieve MRD negativity. Finally, 6 pts (20%) remained MRD[+] at 12m.At 12m FU, the rate of Gr≥2 aGVHD was (11/30) 37% (consecutive to early CsA T&D in 2 pts and to early CsA T&D followed by DLI in 1 pt) and the rate of extensive cGVHD was (5/29) 17% (consecutive to CsA T&D in 1 pt). Hence we observed the occurrence of Gr≥2 aGVHD and extensive cGVHD in 2/8 and 1/8 pts after early CsA T&D. We also observed one case of Gr≥2 aGVHD among the 6 pts who had early CsA T&D followed by DLI. Eighteen severe adverse events were reported, including the 2 aforementioned deaths. These events were not related to the study procedure (PrIm).Discussion These preliminary data highlight the feasibility, safety and efficacy of a standardized PrIm strategy in high-risk CLL. As DLI appears to have limited impact when CsA T&D fails, the preemptive use of new agents should be considered at this point for persistent MRD[+] after 3-6m post-ASCT.Table 1Table 1M12 MRDN%MRD[-] pre-ASCT remaining MRD[-][-]27MRD[+] (M1-2) spontaneously translating to MRD[-] within 3m[-]827MRD[+] (M1-3) translating to MRD[-] after early CsA T&Dconcomitant of severe GVHD (≥G2 aGVHD and/or ext cGVHD)[-]108233MRD[+] (M1-3) remaining MRD[+] despite early CsA T&D followed by DLIdespite early CsA T&D, transient MRD[-], relapse and DLI[+]65120Non evaluable: toxic deaths (2), EBV LPD (1), graft rejection (1)NE413 DisclosuresTournilhac:GSK: Other: Travel Support, Research Funding; Mundiphrama: Honoraria, Other: Travel Support, Research Funding; Celgene: Other: Travel support; Roche: Other: Travel support, Research Funding; Janssen Cilag: Honoraria, Other: Travel support; Gilead: Other: Travel Funding.

Alemtuzumab As Pre-Conditioning Is Safe and Feasible in Patients with T-Cell Lymphoid Neoplasms Undergoing Allogeneic Stem Cell Transplantation

▪Background: In vivo T-cell depletion with Alemtuzumab reduces the incidence of acute and chronic graft-versus-host disease (GvHD) and graft failure, yet it results in an increase of opportunistic infections and delayed immune recovery. In addition, Alemtuzumab has considerable anti-lymphoma activity in T-cell neoplasms.We report on a pilot study analysing the safety and feasibility of Alemtuzumab as pre-conditioning prior to reduced intensity conditioning allogeneic stem cell transplantation (RIC-alloSCT) in patients diagnosed with T-cell non-Hodgkin lymphoma.Methods: Six consecutive patients diagnosed with a T-cell lymphoid malignancy underwent RIC-alloSCT from a HLA-identical sibling (n=5) or a matched unrelated donor (n=1). Diagnosis were Angioimmunoblastic T-cell lymphoma (n=3), hepato-splenic gamma-delta T-cell lymphoma (n=1), T/NK cavum lymphoma (n=2) and Sèzary Syndrome (n=1). All received unmanipulated peripheral blood stem cells; At transplantation 2 patients were in CR, and 4 in PR. Median number of prior regimens was 2 (range 2-5). Conditioning regimen included Fludarabine (5 x 30mg/m2) and Melphalan (2 x 70mg/m2) in all cases. GvHD prophylaxis comprised Cyclosporine A and Methotrexate.The pre-conditioning protocol consisted on 6 escalating doses of intravenous Alemtuzumab starting on day -28 (3 mg on day -28, 10 mg on day -26 followed by four doses of 30 mg on days -24 to -17) given 3 times a week (MWF) on an out-patient basis.Results: Five patients received all six doses of Alemtuzumab as planned whereas one patient received only four doses for logistic reasons related to donor availability. Acetaminophen, Hydrocortisone and Dexchlorpheniramine were administered as pre-medication in all cases with no severe infusional reaction observed. There were no delays in proceeding to SCT conditioning and patients develop no infectious complications during the Alemtuzumab - alloSCT interval.All patients engrafted with a median time to neutrophil engraftment of 23 days (range 14-27). Acute skin GvHD (grade I and III) was observed in 2 patients (33.3%), both obtaining a CR with topical and systemic corticosteroids respectively. Two patients developed mild ocular chronic GvHD (one after subsequent infusions of donor lymphocytes - DLI) but none has suffered from extensive chronic GvHD. No opportunistic infection was observed apart from CMV reactivation that developed in 3 out of 4 seropositive patients (no CMV disease was observed). All patients experienced delayed immune reconstitution (CD4 >200/ul) at a median of 321 days (range 229-518). All 4 patients in PR prior to alloSCT achieved a complete remission. Only one patient (diagnosed with Sèzary Syndrome) experienced a relapsed and responded to DLI. With a median follow-up of 42 months, all patients remain alive and in CR.Conclusions: Our preliminary results suggest that administration of Alemtuzumab prior to reduced intensity conditioning is feasible and safe. In addition to providing T-cell depletion, Alemtuzumab may improve the response rate in T-cell lymphoid malignancies without increasing the risk of infectious complications. These results require further validation in larger phase II studies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Stable long-term pulmonary function after fludarabine, antithymocyte globulin and i.v. BU for reduced-intensity conditioning allogeneic SCT

Lung function decline is a well-recognized complication following allogeneic SCT (allo-SCT). Reduced-intensity conditioning (RIC) and in vivo T-cell depletion by administration of antithymocyte globulin (ATG) may have a protective role in the occurrence of late pulmonary complications. This retrospective study reported the evolution of lung function parameters within the first 2 years after allo-SCT in a population receiving the same RIC regimen that included fludarabine and i.v. BU in combination with low-dose ATG. The median follow-up was 35.2 months. With a median age of 59 years at the time of transplant, at 2 years, the cumulative incidences of non-relapse mortality was as low as 9.7%. The cumulative incidence of relapse was 33%. At 2 years, the cumulative incidences of extensive chronic GVHD (cGVHD) and of pulmonary cGVHD were 23.1% and 1.9%, respectively. The cumulative incidences of airflow obstruction and restrictive pattern were 3.8% and 9.6%, respectively. Moreover, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio remained stable from baseline up to 2 years post transplantation (P=0.26, P=0.27 and P=0.07, respectively). These results correspond favorably with the results obtained with other RIC regimens not incorporating ATG, and suggest that ATG may have a protective pulmonary role after allo-SCT.

Is Early Hematopoietic Stem-Cell Transplantation Necessary in Mantle-Cell Lymphoma?

Is Early Hematopoietic Stem-Cell Transplantation Necessary in Mantle-Cell Lymphoma?

Reduced Intensity Conditioning Allogeneic Stem cell Transplantation (RIC-alloSCT) for Elderly Acute Myeloid Leukaemia (AML) Patients Over 60 Years: A “donor” Versus “no donor” Comparison

AbstractAbstract 2037▪▪This icon denotes a clinically relevant abstractAcute Myeloid Leukemia(AML) in elderly patients is associated with a poor outcome even for patients able to receive intensive chemotherapy. Relapse rate remain elevated around 60 to 80% at 3 years especially in case of unfavourable cytogenetics. From more than 10 years, the approach of RIC-alloSCT has permitted to extend the age limit of transplant in this population. However, feasibility remains controversial for patient aged of 60 years or more because of more frequent co-morbidities translating into an higher risk of treatment related mortality (TRM). To address the question of feasibility and results of RIC-alloSCT in AML patients of 60 years or more in a intend to treat manner approach, we have conducted a retrospective bi-centric analysis based on a comparison “donor” versus “no donor” for patient in first complete remission (CR1). Methods:96 AML were included, all have received a 3+7 or equivalent induction regimen, between 2001–2009 in two different French centers and have benefited of an HLA typing in CR1. All patients of the “donor” group are considered for a RIC-alloSCT after one or two courses of consolidation. Results:The “donor” group is constitute of 30 patients with a median age of 65.5 years and with an HLA identical donor identified. Eighteen 60%) have been finally transplanted with a median period of 188 days from diagnosis to graft. The “no donor” group is constituted by 66 patients with a median age of 68.5. The two groups are similar considering cytogenetics risk and haematological features of the disease.Median follow up is 48 months for alive patients. No difference of overall survival (OS) or Leukemia free survival (LFS) has been observed between the ”donor” and “no donor group” (respectively 51% vs 44%, p=0.7 and 35%vs 32%, p=0.27). When restricting analysis to the patient who could actually received the RIC allo-SCT, the transplant group (n=18) has a significant better outcome for both OS and LFS as compared to the “non transplant” (n=78) group (69% vs 32% and 52% vs 29% respectively). In the transplant group, no patient died from transplant-related mortality. Acute and extensive chronic graft versus host disease (aGVHD and cGVHD) occurred respectively in 5/18 and in 8/18 patients of the “transplant” group. Conclusion:In a intend to treat manner, RIC-alloSCT provides similar outcome as compared to chemotherapy alone in this series of 96 patients. However, both OS and LFS are significantly improved for patients who have actually received RIC-alloSCT. Toxicity appears to be limited in the “transplant” group. Recruiting patients in this study is still ongoing and final results will be presented at the congress. Disclosures:No relevant conflicts of interest to declare.

An Institutional Experience: Correlation Between Absolute Lymphocyte Count and Survival Outcome After Reduced Intensity Conditioning Allogeneic Stem Cell Transplant in Patients with Hematologic Malignancies

Abstract 4541 Background:Allogeneic stem cell transplant (SCT) is currently the standard of care in the consolidative treatment of several hematologic malignancies. Typically after a stem cell transplant the monocytes engraft first, followed by the granulocytes, macrophages and then natural killer cells. Lymphocyte recovery is considered to be an indicator of immune reconstitution during SCT and correlation between rate of recovery of lymphocyte count and patient outcome has been reported in patients after a myeloablative allogeneic transplant. Studies suggest that early lymphocyte recovery may be a predictive marker of engraftment and survival post-myeloablative SCT. However, there is minimal data on lymphocyte recovery after reduced intensity conditioning allogeneic SCT. We report our institutional experience on the correlation between rate of absolute lymphocyte recovery and survival in patients with a hematological malignancy after a reduced intensity conditioning allogeneic SCT. Methods:We performed a retrospective review of all adult patients who underwent reduced intensity conditioning chemotherapy followed by an allogeneic SCT at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University from March 2001 to March 2008. We looked at the post- allograft absolute lymphocyte count (ALC) at 3 different time points – day 15, 21 and 28. Patients were then analyzed based on ALC cutoff values of 200/mm3, 500/mm3 and 1000/mm3. For each of the cutoff values, patients were divided into 2 groups: those with absolute lymphocyte count of less than or equal to the cutoff value and those with ALC of greater than the cutoff value. Results:A total of 131 consecutive patients were included in the analysis; 46.6% were male and 53.4% were female. 51.1% patients underwent matched sibling (MSD) while 48.9% had matched unrelated donor (MUD) SCT. Overall survival was determined in 117 patients; 14 patients were excluded due to incomplete data. At day 15 and 28, patients with an ALC of greater 200/mm3 had a statistically significant overall survival compared to those that were less than 200/mm3, p= 0.016 and p=0.05, respectively. An ALC of greater than 1000/mm3 at day 15 seemed to predict for a worse outcome compared to those with an ALC of less than 1000/mm3 (p=0.008). There were however six times more people in the group with ALC less than 1000/mm3 at day 15, compared to those with ALC greater than 1000/mm3. An ALC of greater than or less than 500/mm3did not significantly appear to affect overall survival at any of the time points evaluated. Conclusion:ALC of greater than 200/mm3 at day 15 and 28 in our patient population appears to be predictive of overall survival after a reduced intensity conditioning stem cell transplant in patients with a hematological malignancy. However, the relationship between ALC and outcome is inconsistent and needs to be explored further in the context of other prognostic factors. Disclosures:No relevant conflicts of interest to declare.

Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience

Despite therapeutic approach that combines rituximab-containing chemotherapy, followed or not by autologous stem cell transplantation (auto-SCT), mantle cell lymphoma (MCL) patients experience relapses. Reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy. We report a multicenter retrospective analysis. Seventy MCL patients underwent RIC-allo-SCT in 12 centers. Median age at transplantation was 56 years and median time from diagnosis to transplantation was 44 months. The median number of previous therapies was 2 (range, 1-5) including autologous transplantation in 47 cases. At time of transplantation, 35 patients were in complete remission, 20 were in partial response and 15 in stable disease or progressive disease. The median follow-up for living patients was 24 months. The 2-year event-free survival (EFS) and overall survival (OS) rates were 50% and 53%, respectively. The 1- and 2-year transplant-related mortality rates were 22% and 32%, respectively. The statistical analysis demonstrated that disease status at transplantation was the only parameter influencing EFS and OS. These results suggest that RIC-allo-SCT may be an effective therapy in MCL patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy. Studies are warranted to investigate the best type of RIC regimen.

Mobilized Peripheral Blood Stem Cells Compared with Bone Marrow as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced-Intensity Conditioning in Patients with Acute Myeloid Leukemia in Complete Remission: An Analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Reduced-intensity conditioning allogeneic stem cell transplant (RIC-alloSCT) is being increasingly used for patients with acute myelogenous leukemia (AML) with comorbidities. Few published data are currently available regarding for the use of peripheral blood stem cells (PBSCs) compared to bone marrow (BM) in the RIC-alloSCT using unrelated donors (URDs). This retrospective report compared the outcomes of PBSC versus BM RIC-alloSCT. Between 2000 and 2007, 602 patients with AML in complete remission (CR) underwent RIC-alloSCT from URDs with PBSC (508) or BM (94) grafts. Recipient's age was higher in the PBSC versus BM groups 57 (range, 17-77 years) and 51 (range, 17-76 years), respectively (P < .0001). Leukemia features and disease status at RIC-alloSCT were also comparable between the PBSC versus BM groups. Engraftment was achieved in 97% and 96% with BM versus peripheral blood (PB), respectively. Acute graft-versus-host disease (aGVHD) grade >II was significantly higher in the PBSC group: 27% versus 12% in the BM group (P < .002). Similarly, chronic graft-versus-host disease (cGVHD; at 2 years) was somewhat higher in the PBSC group with 43% ± 3% versus 35% ± 6% in the BM group, respectively (P = .04). The 2-year probabilities of leukemia-free survival (LFS) were 46% ± 3% for the PBSC group in comparison to 43% ± 6% for the BM transplant group (P = NS), whereas relapse incidence was significantly higher in the BM versus the PB transplant group: 46% ± 6% versus 32% ± 3%, respectively (P = .014). Non-relapse mortality (NRM) was significantly higher for the PBSC versus the BM group: 28% ± 2% versus 13% ± 4%, respectively (P = .004). In multivariate analysis, after adjustment for differences between both groups, the PBSC group was associated with a higher incidence of aGVHD (grade II-IV; hazard ratio [HR] = 2.33; P = .06), higher NRM (HR = 2.3; P = .015), and a decreased relapse incidence (HR, 0.61; P = .02) with no statistical difference of LFS between the 2 groups (P = .88). In conclusion, our results indicate significantly higher incidence of aGVHD and NRM and a lower incidence of relapse but not statistically different LFS comparing unrelated PBSC to BM grafts after RIC-alloSCT.

Cytoreductive treatment with clofarabine/ara‐C combined with reduced‐intensity conditioning and allogeneic stem cell transplantation in patients with high‐risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome

The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.

Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect

Rescue chemotherapy or autologous stem cell transplantation (autoSCT) gives disappointing results in relapsed peripheral T-cell lymphomas (PTCLs). We have retrospectively evaluated the long-term outcome of 52 patients receiving allogeneic SCT for relapsed disease. Histologies were PTCL-not-otherwise specified (n=23), anaplastic large-cell lymphoma (n=11), angioimmunoblastic T-cell lymphomas (n=9) and rare subtypes (n=9). Patients were allografted from related siblings (n=33, 64%) or alternative donors (n=13 (25%) from unrelated and 6 (11%) from haploidentical family donors), following reduced-intensity conditioning (RIC) regimens including thiotepa, fludarabine and cyclophosphamide. Most of the patients had chemosensitive disease (n=39, 75%) and 27 (52%) failed a previous autoSCT. At a median follow-up of 67 months, 27 of 52 patients were found to be alive (52%) and 25 (48%) were dead (n=19 disease progression, n=6 non-relapse mortality (NRM)). The cumulative incidence (CI) of NRM was 12% at 5 years. Extensive chronic graft-versus-host disease increased the risk of NRM (33% versus 8%, P=0.04). The CI of relapse was 49% at 5 years, influenced by disease status at the time of allografting (P=0.0009) and treatment lines (P=0.007). Five-year overall survival and progression-free survival (PFS) were 50% (95% CI, 36 - 63%) and 40% (95% CI, 27 - 53%), respectively. The current PFS was 44% (95% CI, 30-57%). In all, 8 out of 12 patients (66%) who received donor-lymphocytes infusions for disease progression had a response. At multivariable analysis, refractory disease and age over 45 years were independent adverse prognostic factors. RIC allogeneic SCT is an effective salvage treatment with a better outcome for younger patients with chemosensitive disease.

Conditioning with Fludarabine, Busulfan, and ATG Prior to Reduced-Intensity Allogeneic Stem Cell Transplant for CLL Is Associated with a Low Incidence of Acute Graft-Versus-Host Disease.

AbstractAbstract 4568 Introduction:Allogeneic stem cell transplant (SCT) is the only potentially curative treatment available for CLL. While transplant-related mortality has decreased with use of reduced-intensity conditioning (RIC) regimens, acute and chronic graft-versus-host-disease (GVHD) remain important causes of morbidity and mortality, with up to 50% of patients developing chronic GVHD (cGVHD). While the optimal way to combat this has not been established, in vitro T cell depletion with ATG or alemtuzumab has been employed to attempt to lessen its incidence. Herein, we report our institutional experience with each of these agents. Patients and methods:Information on all patients who underwent RIC allogeneic SCT at Ohio State from January 1, 2002 to June 29, 2010 was obtained following approval from the ORRP. Data collected by the transplant coordinators was correlated with data in our electronic databases. Comparative statistics were performed using the Fisher exact test and all p-values are two-sided. Results:Between January 1, 2002 and June 29, 2010, 50 patients with CLL/SLL underwent RIC allogeneic SCT at Ohio State. Pretransplant characteristics are listed in Table 1. Thirty patients received fludarabine, busulfan, and ATG (FBA) as a preparative regimen, and 8 patients received alemtuzumab, fludarabine, and TBI (Cam/Flu/TBI). Another 6 patients received fludarabine and busulfan, 4 received fludarabine and cyclophosphamide, one received pentostatin, fludarabine, and ATG, and the patient who had a cord blood transplant received fludarabine, cyclophosphamide, TBI, and ATG. The breakdown of characteristics between patients who received FBA and Cam/Flu/TBI is also provided in Table 1. None of the characteristics were statistically different. Time to count recovery is provided in Table 2. There was not a statistically significant difference in the time to count recovery between FBA and Cam/Flu/TBI. Patients who received Cam/Flu/TBI received significantly more DLIs; patients who received FBA have not required any DLIs. Incidence of acute and chronic GVHD is provided in Table 3. There was not a statistically significant difference in rates or grades of aGVHD, but patients who received Cam/Flu/TBI were more likely to develop extensive cGVHD. Conclusions:While patients who received Cam/Flu/TBI were more likely to receive DLI, these were all done to treat disease recurrence, reflecting changes in group practice over time. There were no failures to engraft with FBA, and while not statistically significant in comparison to Cam/Flu/TBI, only 10% of patients developed grade 3 or 4 aGVHD. All of the patients who received Cam/Flu/TBI and developed cGVHD developed extensive disease. While the Cam/Flu/TBI sample is small, the FBA patients appear to fare no worse in terms of count recovery and development of GVHD without exposure to TBI, and this has become our institutional practice for patients with CLL.Table 1Pretransplant characteristicsTotal n=50Flu/Bu/ATG n=30Cam/Flu/TBI n=8p valueMedian age595949.5range38–7443–7446–69SexM38 (76%)25 (83%)5 (63%)F12 (24%)5 (17%)3 (37%)Median KPS909090Disease statusCR1 (2%)1 (3%)0PR29 (58%)18 (60%)5 (63%)SD1 (2%)1 (3%)0Rel2 (4%)2 (6%)0Ref17 (34%)8 (27%)3 (37%)Cytodel13q5 (10%)4 (13%)1 (13%)normal8 (16%)3 (10%)1 (13%)trisomy 123 (6%)01 (13%)del11q10 (20%)5 (17%)2 (25%)del17p24 (48%)18 (60%)3 (37%)Median # therapies443Median time from dx to tx(days)141114151143Stem cell sourceBM1 (2%)1 (3%)0CB1 (2%)00PB48 (96%)29 (97%)8 (100%)Donor sourceHLA-matched sib21 (42%)7 (23%)5 (63%)HLA-mm sib1 (2%)1 (3%)0HLA-matched unrel24 (48%)19 (63%)3 (37%)HLA-mm unrel3 (6%)3 (10%)0Median CD34+ dose5.216.25.06Median CD3+ dose2.132.092.415GVHD prophFK/MTX42 (84%)30 (100%)0FK/MMF8 (16%)08 (100%)Table 2Time to count recoveryTotal n=48Flu/Bu/ATG n=30Cam/Flu/TBI n=8p valueANC <500≤ 15 days19 (40%)10 (33%)2 (25%)>15 days29 (60%)20 (67%)6 (75%)0.7Plts <20≤ 15 days34 (71%)21 (70%)6 (75%)>15 days14 (29%)9 (30%)2 (25%)1DLI5 (10%)05 (63%)<0.001Table 3Acute and chronic GVHDTotal n=45Flu/Bu/ATG n=27Cam/Flu/TBI n=8p valueaGVHD32 (71%)20 (74%)7 (88%)0.65Grade 1-227 (84%)18 (90%)5 (63%)Grade 3-45 (16%)2 (10%)2 (25%)0.55cGVHD23 (51%)12 (44%)5 (63%)0.44Limited10 (22%)7 (26%)0Extensive13 (29%)5 (19%)5 (63%)0.04 Disclosures:Lin:GlaxoSmithKline: Consultancy, Employment.

Therapeutic options for patients with myelofibrosis in blast phase

Myelofibrosis (MF) is a clonal stem cell disorder with the potential to transform to acute leukemia, referred to as myelofibrosis in blast phase (MF-BP). The outcome of patients with MF-BP is grave with a median survival of only 2.7 months. MF-BP is largely refractory to conventional chemotherapy and intensive induction therapy fails to have a significant impact with a median survival of 3.9 months. Eleven consecutive patients were treated at our institution with MF-BP over a 2-year period. Eligible patients with an available donor received an allogeneic stem cell transplant (ASCT) and those that were not eligible or without a donor were treated with Decitabine (DEC). The median time for follow up for the entire group was 9 months (range 5–21 month). At 9 months (range 5–45 months), 67% of the patients treated with DEC were alive and at 20 months (range 9–23 months), 53% of patients treated with ASCT remain alive. Reduced intensity conditioning allogeneic stem cell transplantation (RIC-ASCT) is a viable option that offers the potential for prolonged survival and the possibility of cure for patients with MF-BP. DEC is a tolerable outpatient chemotherapeutic regimen for MF-BP patients ineligible for transplant and deserves further prospective study.

Late onset cytomegalovirus encephalitis after reduced-intensity conditioning allogeneic SCT: an emerging neurological complication?

Late onset cytomegalovirus encephalitis after reduced-intensity conditioning allogeneic SCT: an emerging neurological complication?

90y-ibritumomab tiuxetan followed by reduced-intensity conditioning (RIC) and allogeneic stem-cell transplantation (SCT) in patients with high-risk relapsed, refractory, or transformed follicular lymphoma (FL).

6538 Background: The use of RIC SCT in relapsed, refractory or transformed FL is associated with higher relapse rates but similar overall survival (OS) when compared to myeloablative SCT. Radioimmunoconjugates prior to RIC allogeneic SCT may provide sufficient early cytoreduction while allowing for long-term disease control through graft versus lymphoma effect without the associated toxicity of a myeloablative SCT in this older, often heavily pretreated patient population. Methods: We performed a retrospective study to describe the baseline characteristics and outcomes of twelve patients with relapsed, refractory or transformed FL who received 90Y ibritumomab tiuxetan followed by fludarabine and low-dose busulfan RIC allogeneic SCT at the Dana-Farber Cancer Institute between 2006 and 2009. Results: Twelve patients were identified with a median age of 55 (40-66) years and a median number of lines of therapy of 5 (2-10). Three (25%) had chemorefractory FL and two (17%) had transformed to a more aggressive histology. Nine patients (75%) received SCT from unrelated donors. The median follow-up is 24 months (range, 3-42). The median time from 90Y ibritumomab tiuxetan to SCT was 1.0 month (range 0.4-5.8). Two (17%) and four (33%) patients did not reach a nadir for PMN and platelets, respectively. All patients engrafted with a median time to PMN and platelet engraftment of 14 days (n = 10; range 11-35) and 20 days (n = 8; range 11-163), respectively. Conclusions: Ten patients (83%) achieved a complete response (CR) and two patients achieved a partial response (PR). Two patients died from infection (n = 1) and graft versus host disease (GVHD) (n = 1). One patient relapsed. Cumulative incidences of grade II-IV acute GVHD at 200 days were 28% (± 15%) and chronic GVHD at 12 months were 67 % (± 18%). Two-year non-relapse mortality was 20% (± 14%). Two-year OS and progression-free survival were 80% (± 13%) and 69% (± 15%), respectively.This treatment is associated with favorable outcomes including acceptable rates of GVHD and relapse in this high-risk patient population and warrants prospective studies. No significant financial relationships to disclose.

Evaluation Of Busulfan's Dose-Intensity In Patients Undergoing Allogeneic Stem Cell Transplantation (ASCT) With Two Different Fludarabine/Busulfan/ATG (FBA)-Based Reduced Intensity Conditioning (RIC) Regimens

We evaluated the effects of busulfan's dose-intensity in patients undergoing RIC ASCT at two different transplant centers. Forty-three patients were conditioned with busulfan (0.8mg/kg/dose IV × 8 doses), fludarabine (30mg/m2/day, days -7 to -3), and 6mg/kg of ATG (L-FBA), while 23 patients received a ‘more-intense’ RIC with busulfan (130mg/m2/day IV, days -6 to -3), fludarabine (40mg/m2/day, days -6 to -3), and 6mg/kg of ATG (H-FBA). Median age was 55 years. 84% (N=56) had high-risk disease. 19 patients (29%) received mismatched allografts.

Reduced-intensity conditioned allogeneic haematopoietic stem cell transplantation results in durable disease-free and overall survival in patients with poor prognosis myeloid and lymphoid malignancies: eighty-month follow-up

The long-term outcome of patients with haematological malignancies treated with reduced-intensity conditioned allogeneic peripheral blood stem cell transplantation is not known. We report the outcome of 79 patients with poor-risk myeloid and lymphoid malignancies transplanted with reduced-intensity conditioning (RIC) regimens. The diagnoses include AML/myelodysplastic syndrome (n=43), non Hodgkin's lymphoma (n=30), Hodgkin's lymphoma (n=3), ALL (n=2) and CML (n=1). For the entire cohort, the disease-free survival (DFS) and OS were 61.2 and 35.7%, respectively. Twenty patients relapsed, 18 within the first three years, and 14 patients succumbed to progressive disease. Overall, 31 patients died from transplant-related complications within the first three years. Day 100 non-relapse mortality correlated with a higher total nucleated cell dose in the graft (odds ratio: 3.9). For those in CR at 3 years, the DFS and OS were 84.2 and 81.1%, respectively. Furthermore, of 43 patients with active disease at the time of transplantation, 16 remained in CR after 3 years. The majority of the long-term survivors were functioning independently. One patient died from a second malignancy. No post-transplant lymphoproliferative disorder was seen. In conclusion, durable disease control was achieved after RIC allogeneic stem cell transplantation for patients with advanced myeloid and lymphoid malignancies.