Busulfan/Fludarabine/Thymoglobulin as a Reduced Intensity Conditioning Regimen for Lymphoid Malignancies.

Abstract Abstract 3335 Poster Board III-223 Introduction Over the last decade there has been an increase in the use of reduced intensity conditioning (RIC) regimens to mitigate transplant related toxicity while maintaining graft viability and maximizing the graft versus disease effect. There is an abundance of data on busulfan (Bu) based RIC for myeloid malignancies; however, there is a paucity of data on Bu based RIC regimen for allografting in lymphoid malignancies. We conducted a retrospective analysis of a large cohort of patients treated at a single institution who were transplanted using a uniform RIC regimen of Bu/Fludarabine (Flu)/Thymoglobulin (Thymo) for a variety of lymphoid neoplasms. Methods We identified 40 patients (pts) who were transplanted for lymphoid malignancies between 2004 and 2008 using the RIC regimen of Bu 0.8 mg/kg q6 hrs x 8 doses on d-4 and d-3, Flu 30 mg/m2 IV daily on days -7 to -3, and Thymo 2 mg/kg x 4 doses on d-4 to d-1. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus (0.03 mg/kg starting d-2)/methotrexate (5mg/m2 on d+1, 3, 6, 11)/mycophenolate (15mg/kg bid starting d-2) in 34 pts (85%), tacrolimus/methotrexate in 5 patients (12.5%), cyclosporine/mycophenolate/methotrexate in 1 pt (2.5%). Chimerism analysis was done on days +30, 90, 180, and 365. Demographics Median age was 54 (range 35-65) years; males 26 (65%) and females 14 (35%); CLL/SLL 22 (55%), non-Hodgkins lymphoma 15 (37.5%) and transformed lymphomas 3 (7.5%). Median number of lines of therapy prior to transplant was 4 (range 0-12). 12 pts (30%) were refractory to initial therapy (less than a PR). 15 pts (37.5%) had received prior radiation therapy (XRT). 12 pts (30%) had undergone a prior autologous stem cell transplant (ASCT). 22 pts (55%) had chemo-sensitive disease at the time of transplant, and 18 (45%) had disease refractory to their pre-transplant regimen. The donor was related (RD) in 10 pts (25%) and unrelated (URD) in 30 pts (75%). The graft source was peripheral blood for 36 pts (90%) and bone marrow in 4 pts (10%). Median number of CD34+ cells infused was 7.9×10 6 (range, 1.1-17.9) /kg recipient body wt. Results Median time to absolute neutrophil count recovery was 12 (0-21) days. Median time to platelet recovery was 18 days (9-57 days). Median time to 100% donor chimerism was 39 (24-321) days. After a median follow-up of 25.8 (0.87-48.9) months, Kaplan-Meier estimates of median overall survival (OS) and progression-free survival (PFS) were 11.3 months and 9.9 months, respectively. The 2-yr OS and PFS were both 44%. We performed an analysis of the effects of histology, number of lines of prior therapy, prior XRT, prior ASCT, disease status at time of transplant, and graft source (URD vs RD) on OS and PFS (Table 1). Non-relapse mortality (NRM) at 100 days, 1 year, and 2 years was 8% (95% CI, 3-22%), 33% (95% CI, 20-52%), and 41% (95% CI, 26-60%), respectively. Acute GVHD was seen in 19 pts (48%) with Grade III/ IV acute GVHD in 9 pts (23%). Chronic GVHD was seen in 17 pts (43%), limited in 5 pts (13%), extensive in 12 pts (30%). Acute GVHD was more common among pts receiving URD vs RD transplants (35% vs. 13%, p=0.016), but incidence of chronic GVHD did not differ between these two cohorts. Conclusion This analysis represents the largest single institution experience using the RIC regimen of Bu/Flu/Thymo in lymphoid malignancies. Our results demonstrate that this Bu based RIC regimen can successfully be used to allograft heavily pre-treated patients with lymphoid malignancies, with prompt and durable engraftment and relatively low early NRM. In this patient population, OS and PFS were not significantly associated with lymphoma histology, prior therapy, or chemosensitivity. Disclosures DiPersio: Genzyme Corp.: Honoraria. Vij:Otsuka Pharmaceuticals: Research Funding.

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Peri-Transplant Administration of Ruxolitinib Is Safe and Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib Administration in Combination with Reduced Intensity Conditioning

Blood ◽

10.1182/blood-2019-127445 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 669-669 ◽

Cited By ~ 3

Author(s):

Haris Ali ◽

David Snyder ◽

Tracy Stiller ◽

Timothy Synold ◽

Saloomeh Mokhtari ◽

...

Keyword(s):

Pilot Study ◽

Median Time ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

Cell Transplant ◽

Reduced Intensity Conditioning ◽

Grade 3 ◽

Reduced Intensity

Ruxolitinib (Rux), a potent JAK1/2 inhibitor, is the only FDA-approved drug for treatment of primary and secondary myelofibrosis (MF). Rux has been recently approved for treatment of steroid refractory acute graft-versus-host disease (GVHD), a major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). In MF patients proceeding with transplant, Rux is typically discontinued pre-HCT. Given the therapeutic, immunologic, and anti-inflammatory properties of Rux, we hypothesized that continuous peri-HCT administration of the drug is safe and can result in better transplant outcomes in MF patients. Here, we are reporting outcomes of our single arm, single center pilot study (NCT02917096) investigating the safety and efficacy of Rux administration in patients with primary or secondary MF undergoing HCT with fludarabine (125 mg/m2) and melphalan (140 mg/m2) as reduced intensity conditioning and sirolimus/tacrolimus (target levels: 5-10ng/ml for both) as GVHD prophylaxis. This pilot study is being conducted in MF patients with the goal of extending the therapy to other hematologic malignancies. The primary objective was to identify the maximum tolerated dose and recommended phase II dose. Rux was given at 2 dose levels (DL) of 5 and 10 mg BID, starting from day -3 pre-HCT until day +30 post-HCT, then tapered off by day +33. DLs were chosen based on previous retrospective studies identifying the drug dose for treatment of GVHD. Primary endpoint was safety. Dose limiting toxicity (DLT) was defined as grade 4 neutropenia associated with fever, infection, or engraftment failure or any grade ≥3 non-hematologic toxicities over 45 days. Key secondary endpoints were grade 2-4 acute GVHD, engraftment, infection, overall survival (OS), progression-free survival (PFS), NRM, relapse and chronic GVHD. So far, we have enrolled 12 patients: 6 for DL1 arm and 6 for DL2. Median age at the time of HCT was 53 years (range: 25-66) for DL1 and 68 years (range: 56-72) for the DL2 arm. Detailed patient/transplant characteristics are listed in table 1. One-year OS, PFS and NRM for all patients were 80% (95%CI: 39-95), 68% (95%CI: 30-89) and 21% (95%CI: 3-50), respectively. All patients engrafted (n=12), with the median time to neutrophils engraftment of 19 days (range: 13-23) for DL1 and 16 days (range: 12-22) for the DL2 arm. Hematologic DLTs were not observed in patients at either dose level. At DL1, by day +60, grade ≥3 toxicities were cardiac (n=1), pulmonary (n=1) and gastrointestinal (n=1). Only one case of grade ≥3 pulmonary toxicity was observed in patients at DL2. After median follow-up time of 373 days (range: 365-744) in DL1 and 98 days (range: 30-379) for DL2, there were two deaths; one due to respiratory failure in DL1, and another due to acute GVHD at DL2. Median time of acute GVHD onset was 20 days (range: 19-35) in DL1 and 51 days (range: 26-76) in DL2. Grade III-IV acute GVHD was seen in only 1 out of 12 patients and grade 1 acute GVHD was seen in 4 patients. One patient in DL1 relapsed at 9 months and re-entered remission with post-HCT treatment. CMV infection was seen in only 1 patient at DL2. Pharmacokinetics (PK) studies were done for five patients at DL1 and all patients at DL2. PK was dose-proportional, in which doubling of the dose corresponded to the twice greater Cmax and AUC. The half-lives and oral clearances were not different between the two DLs. The Cmax and AUC were lower in our patients compared to a previously published report in healthy volunteers. Furthermore, the elimination half-life was similar to the published data, indicating that the lower drug exposures measured on the current trial is most likely due to decreased oral absorption. Lastly, GVHD biomarkers and inflammatory cytokines levels were not different between patients receiving Rux at DL1 and DL2. In conclusion, early results of this pilot study indicate that Rux administration at 10 mg BID in MF patients undergoing HCT is safe and feasible, with 100% engraftment and low rate of acute GVHD. We are currently accruing an expansion cohort of 6 patients at DL2. Results of our PK studies indicated a direct correlation between Cmax and AUC and that higher oral clearance compared to previous study is most likely due to poor GI absorption of the drug in HCT patients. More follow up is needed to see the impact of this combination on incidence of chronic GVHD. This regimen may also be useful for patients undergoing HCT for other hematologic malignancies. Disclosures Palmer: Gilead Sciences: Consultancy. Salhotra:Celgene: Other: Research Support; Kadmon Corporation: Other: Non paid consultant. Mei:Seattle Genetics, Inc.: Research Funding. Nakamura:Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Merck: Membership on an entity's Board of Directors or advisory committees; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

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Characterization of Chronic Graft-Versus-Host Disease and Duration of Immunosuppression After Cord Blood Transplantation,

Blood ◽

10.1182/blood.v118.21.4077.4077 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4077-4077

Author(s):

Laura F Newell ◽

Mary E.D. Flowers ◽

Ted Gooley ◽

Filippo Milano ◽

Paul A. Carpenter ◽

...

Keyword(s):

Cord Blood ◽

Median Time ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Cell Transplant ◽

Gi Tract ◽

Reduced Intensity Conditioning ◽

Host Disease ◽

Graft Versus Host ◽

Reduced Intensity

Abstract Abstract 4077 Background: The reported incidence of chronic graft-versus-host disease (cGVHD) after cord blood transplant (CBT) varies widely in the literature, with some studies suggesting that cGVHD is more responsive to treatment after CBT than after conventional hematopoietic cell transplant (HCT). The 2005 National Institutes of Health (NIH) consensus criteria were designed to standardize the diagnosis and scoring of cGVHD. While these criteria have been used to evaluate GVHD after bone marrow (BMT) and mobilized blood (PBSCT) cell transplantation, analysis of GVHD after CBT by NIH criteria has been limited. We report the results of a single-center, prospective analysis of GVHD evaluated according to the NIH diagnostic criteria in adults and children receiving unrelated CBT after high or reduced-intensity conditioning. Methods: Eighty-seven consecutive patients who received a first single or double CBT between 2006 and 2011 were included. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Grafts were HLA-typed at the antigen level for HLA-A and B, and high resolution for HLA-DRB1. Patients were prospectively evaluated for GVHD at day 80, 1-year, and at any other time as clinically indicated. Results: Median patient age was 31 years (range 0.8–70). Diagnosis at transplant included AML (n=49), ALL (n=20), CML (n=5), MDS/MPD (n=5), and other hematologic malignancy (n=8). The median follow-up after CBT was 24 months (range 1–127). Most patients received high-intensity conditioning (79%, n=69) and a double CB graft (86%, n=75). HLA-matching was 4/6 in 59% (n=51) of patients, 5/6 in 37% (n=32), and 6/6 in 4% (n=4). Median total infused cell doses were: 3.8 × 107 TNC/kg, 0.21 × 106 CD34+ cells/kg, and 10.9 × 106 CD3+ cells/kg. Neutrophil engraftment occurred in 90% of patients (n=78), at a median of 22 and 13 days after high and reduced-intensity conditioning, respectively. The cumulative incidence (CI) of grades II-IV and III-IV acute GVHD (aGVHD) was 74.7% and 29.9%, respectively. Sixty-eight patients (78%) were alive, engrafted with donor cells, and without relapse at day 80. Fifty-four patients had GVHD requiring systemic immunosuppressive treatment after day 80, for an estimated 2-year CI of 64%. Most patients had quiescent or interrupted onset (69%) and 48% had thrombocytopenia at time of diagnosis. By NIH criteria, 25 patients presented with “late” acute GVHD, and 29 presented with NIH cGVHD. Two patients who presented with “late” acute GVHD subsequently developed NIH cGVHD (Figure 1). Most patients with “late” acute GVHD had recurrent acute GVHD (n=20) with a median onset at 141 days after CBT (range 77–599). Organs affected by “late” acute GVHD were the GI tract (n=17), skin (n=12), and liver (n=5). Of the 31 patients with NIH cGVHD, 7 developed only the classic subtype with a median onset at 123 days after CBT (range 91–363). Organs affected in patients with classic NIH cGVHD were mouth (n=5), skin (n=5), lung (n=1), serosa (n=2), and genital (n=1). Most patients with NIH cGVHD had the overlap subtype (n=24), occurring at a median of 114 days after CBT (range 80–412). Organs involved in the overlap subtype included the GI tract (n=22), liver (n=7), acute skin (n=9), chronic skin (n=6), mouth (n=21), eyes (n=3), lung (n=1), esophagus (n=1), and serosa (n=3). The estimated 3-year CI of discontinuing immunosuppressive therapy (IST) while alive without relapse was 52%, while the 3-year estimated CI of death or relapse during IST was 33% (Figure 2). Among those who discontinued IST, the median time from onset of late acute GVHD or NIH cGVHD to discontinuation of IST was 12 months. In a previous study, the median time to discontinuation of IST for patients with cGVHD after BMT or PBSCT was 23 months. Conclusions: Despite a highly HLA-mismatched donor source, the CI of cGVHD after CBT is comparable to that after conventional HLA-matched unrelated donor HCT previously reported from our center. Our results indicate that GVHD occurring after day 80 post CBT frequently manifests itself as acute GVHD predominantly involving the GI tract. More importantly, these preliminary results suggest that time to resolution of GVHD diagnosed after day 80 appears to be shorter after CBT compared to after BMT or PBSCT. Disclosures: No relevant conflicts of interest to declare.

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Outcome of Second Allogeneic Transplants Using Reduced Intensity Conditioning Following Relapse after an Initial Allogeneic Transplant.

Blood ◽

10.1182/blood.v108.11.3660.3660 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3660-3660

Author(s):

B.E. Shaw ◽

G.J. Mufti ◽

S. Mackinnon ◽

J. Cavenagh ◽

K. Towlson ◽

...

Keyword(s):

Median Time ◽

Acute Gvhd ◽

Chronic Gvhd ◽

British Society ◽

Disease Relapse ◽

Allogeneic Transplant ◽

Reduced Intensity Conditioning ◽

Relapse Risk ◽

Time To Relapse ◽

Reduced Intensity

Abstract The management of disease relapse following an allogeneic transplant is problematic. For patients with some diseases treatment with DLI alone can be successful. The use of a second allogeneic procedure has been associated with a prohibitively high TRM, especially when using myeloablative conditioning. Here we report the results of a British Society for Blood and Marrow Transplantation (BSBMT) registry retrospective multicentre analysis of 70 patients receiving a second allogeneic transplant using reduced intensity conditioning (RIC) after disease relapse following an initial allogeneic transplant. In 41 cases the first procedure was myeloablative and in 17 this was with RIC (unknown: 12). Over half of the first grafts were T cell depleted (TCD). The donor was an HLA identical sibling (48), unrelated (17) or other family member (2). In 11 cases a different donor was used at second transplant. The median age at first transplant was 39 (range: 8–69). The underlying diseases are as follows: AML 21, MDS 13, ALL 13, Lymphoma 11, CML 7, MPD 3, MM 2. For the second transplant, a variety of RIC regimens were used. Of these, 85% were fludarabine based and less than 20% include TCD. At the time of analysis, 27 patients were alive at a median follow-up of 1.7 years from second allograft (range: 0.3–7.4 years). In the cohort overall, the predicted overall survival and TRM at 2 years post second allograft were 27% and 27% respectively. Disease type was significantly associated with outcome (OS 1yr: lymphoma 82%, AML 32%, MDS 39%, ALL 41%, p=0.049). Age and disease status did not impact on OS or TRM. The median time to relapse after the first transplant was 1 year (range: 0.1–12.2). There was a significant survival advantage to those who relapsed more than a year post first allograft (2yr post second allograft: 33% vs 21%, p=0.038). In addition, patients with later relapses had a TRM of 12% at 2 years compared to 39% in those relapsing within a year (p=0.009). The incidence of acute GvHD was higher following the second procedure (43%) than the first (28%). Although aGvHD at any time did not impact on OS in the whole cohort, in those who relapsed prior to a year the presence of acute GvHD post second allograft was significantly associated with a superior outcome (p=0.001). The median time to relapse from the second transplant was 0.73 years (range = 0.1 – 1.6). The predicted relapse risk post second transplant was 52 % at 2 years. Those under the median age (p=0.029) and with acute leukaemia (1 yr post second transplant risk: AML 57%, MDS 34%, ALL 54%, lymphoma 14%; p=0.056) were at higher risk. Remission status prior to either transplant, acute or chronic GvHD post second allograft, donor type and time to first relapse did not impact significantly on relapse risk. In conclusion, compared to second myeloablative transplants, a second allograft using RIC can be performed with a low TRM in those relapsing more than one year after a first allograft, even when using UD. These patients achieved an encouraging OS of > 30% at 2 years. In those relapsing within a year of first transplant the development of GvHD was strongly associated with a better outcome.

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Improved Outcomes Using Tacrolimus/Sirolimus for graft Versus Host Disease prophylaxis with a Reduced Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant for Myelofibrosis

Blood ◽

10.1182/blood.v112.11.4410.4410 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4410-4410

Author(s):

David S. Snyder ◽

Joycelynne Palmer ◽

Karl Gaal ◽

Anthony Selwyn Stein ◽

Vinod Pullarkat ◽

...

Keyword(s):

Acute Gvhd ◽

Hematopoietic Cell ◽

Cell Transplant ◽

Reduced Intensity Conditioning ◽

Host Disease ◽

Gvhd Prophylaxis ◽

The Impact ◽

Kinase Mutation ◽

Reduced Intensity

Abstract Allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) regimens is a potentially curative treatment for patients (pts) with myelofibrosis (MF), as we (BBMT12:1161,2006) and others have reported. Treatment related mortality (TRM) from Graft vs. Host Disease (GVHD) and other complications has limited the success of this approach. We have recently utilized a combination of tacrolimus(tacro)/sirolimus (siro) +/− methotrexate (MTX) for GVHD prophylaxis in a cohort of 14 consecutive pts with MF treated with RIC HCT at City of Hope in an effort to reduce TRM from GVHD and related complications. In this report, we present results for 23 pts including extended follow up for the previously reported 9 pts who received cyclosporine (CSA)/mycophenolate (MMF) +/− MTX, and the current cohort of 14 pts who received tacro/siro +/− MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. MTX was included for all recipients of matched unrelated donor (MUD) products. The cohort median age was 58 yrs (range 39–69) with 12 females, 11 males. Two of nine CSA/MMF pts developed MF secondary to a prior myeloproliferative disorder and 3/14 tacro/siro pts had secondary MF. The Lille risk score was high for 10 pts, intermediate for 12, and low for 1. The RIC regimen consisted of Fludarabine/melphalan for 23 pts, including all 14 of the tacro/siro pts, and fludarabine/total body irradiation for the first pt in the CSA/MMF cohort. Eight pts received stem cell products from HLA matched siblings (2/9 CSA/MMF pts; 6/14 tacro/siro pts) and 15 from MUDs (7/9 CSA/MMF pts; 8/14 tacro/siro pts). The source of stem cells was GCSF primed peripheral blood for 21 pts, and unprimed bone marrow for 2 pts. The median cell dose was 7.8 × 10^6 CD34 cells/kg. Median follow up for alive patients was 26.7 mos (3.4–97.6). All evaluable pts engrafted with neutrophils (median 16.5 days) and platelets (median 18.0 days). Chimerism studies demonstrated donor engraftment in 94–100% of cells using STR or FISH analysis. JAK 2 kinase mutation analysis was available pre-HCT for 4/14 pts in the tacro/siro cohort. Two of these four pts were positive, and both became JAK2 kinase mutation negative post-HCT. No pt in either cohort relapsed, and none developed veno-occlusive disease or thrombotic microangiopathy. Five pts died- 4 from GVHD +/− infections or multi-organ failure and one from graft failure with sepsis. The estimated 2 yr overall survival (OS) for the CSA/MMF cohort was 66.7 %(confidence intervals 20.4,80.5), and for the tacro/siro cohort it was 92.3% (56.6,98.9) (p=0.0472). The probability of grade III or IV acute GVHD was 60% for the CSA/MMF pts, and 10% for the tacro/siro group (p=0.0102). The 100-day TRM was 33.3% for the CSA/MMF pts and 0 for the tacro/siro group (p=0.0215). Five of the six evaluable pts in the CSA/MMF cohort developed chronic GVHD (4/5 extensive) compared to 9/14 pts (6/9 extensive) in the tacro/siro group. We conclude that the combination of tacro/siro +/− MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to lead to improved OS compared to CSA/MMF +/− MTX, and that this benefit may be due to a significant decrease in the incidence of severe acute GVHD with the use of tacro/siro +/− MTX.

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Flavopiridol Is An Effective Therapy to Bridge Patients with Chronic Lymphocytic Leukemia (CLL) to Reduced-Intensity Conditioning Allogeneic Stem Cell Transplant

Blood ◽

10.1182/blood.v116.21.2383.2383 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2383-2383 ◽

Cited By ~ 2

Author(s):

Samantha M. Jaglowski ◽

Joseph M. Flynn ◽

Jeffrey A. Jones ◽

Thomas S. Lin ◽

Beth Fischer ◽

...

Keyword(s):

Stem Cell ◽

Kinase Inhibitor ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Cell Transplant ◽

Reduced Intensity Conditioning ◽

Major Barrier ◽

Curative Therapy ◽

Reduced Intensity

Abstract Abstract 2383 Introduction: Allogeneic stem cell transplantation (SCT) is the only potentially curative therapy for patients with CLL. We reported that a major barrier to patients receiving SCT is an inability to attain the necessary disease control with available salvage regimens to proceed to transplant, emphasizing the need to continue to look for alternative therapies. Flavopiridol, a cyclin-dependent kinase inhibitor that induces apoptosis independently of p53, is one such alternative. We sought to determine the outcomes of transplant in patients who had received flavopiridol. Patients and methods: Patients included in this evaluation were enrolled on OSU 0055, 0491, 0211, or 06124 and went on to receive allogeneic SCT. Survival curves were performed using the Kaplan-Meier method. PFS and OS were calculated from the date of the transplant. Results: Of the 50 patients who underwent reduced-intensity conditioning (RIC) allogeneic SCT at Ohio State between January 1, 2002 and June 29, 2010, 19 received flavopiridol prior to transplant; nine responded and proceeded directly to transplant. Ten patients received further treatment after flavopiridol: 6 patients had progressive disease, 3 were removed from protocol, and 1 had a prolonged response. Pre-transplant characteristics are summarized in Table 1. Notably, 78% of responders had del(17p13.1), and 33% had bulky lymphadenopathy prior to treatment with flavopiridol. Patients received a median 5 lines of treatment (range 2–11) prior to transplant. Transplant results are summarized in Table 2. After a median observation period of 17.2 months following transplant (range 0.2–39.9), 10 patients were still alive, 5 of whom responded to flavopiridol. Four deaths were due to complications of the transplant, and 3 were due to disease progression. The median time to ANC recovery > 500 was 16 days. Seventeen patients were evaluable for response. Seven patients (41%) had CR following transplant, 6 of whom were MRD-negative. Four of the MRD-negative patients in CR had responded to flavopiridol. Acute GVHD was primarily grade 2 or less, and 50% of patients did not develop chronic GVHD. KM estimates of overall and progression-free survival are included in Figures 1 and 2. Estimated median OS overall is 19.8 months with PFS of 18.6 months; the median OS for the subset of patients who responded to flavopiridol was 34.9 months with median PFS of 29.2 months. Conclusions: Flavopiridol was effective for inducing a disease response in this group of heavily pretreated patients, the majority of whom had del(17p13.1), the sole cytogenetic indication for transplant in first remission in CLL. The patients who responded to flavopiridol and could proceed directly to transplant had longer OS and PFS, although this was not statistically significant. Furthermore, we have observed that flavopiridol is associated with low occurrence of infection when compared with available salvage regimens and thus represents an effective strategy to bridge patients to transplant in a timely manner. Disclosures: Jones: GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding. Lin: GlaxoSmithKline: Consultancy, Employment.

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Reduced Intensity Conditioning with Combined Haploidentical and Cord Blood Transplantation Results in Rapid Engraftment and Durable Remissions in Hematological Malignancies

Blood ◽

10.1182/blood.v118.21.830.830 ◽

2011 ◽

Vol 118 (21) ◽

pp. 830-830

Author(s):

Hongtao Liu ◽

Elizabeth Shima Rich ◽

Lucy Godley ◽

Olatoyosi Odenike ◽

Loren Joseph ◽

...

Keyword(s):

Cumulative Incidence ◽

Hematological Malignancies ◽

Chronic Gvhd ◽

Median Number ◽

Reduced Intensity Conditioning ◽

Cell Content ◽

Median Percentage ◽

One Year ◽

Active Disease ◽

Reduced Intensity

Abstract Abstract 830 Haplo-cord transplant, the co-infusion of CD34+ stem cells from a haploidentical (haplo) family member with a cord blood (UCB) unit has been proposed as a method to reduce duration of pancytopenia after UCB SCT. We prospectively investigated reduced intensity conditioning (RIC) of fludarabine, melphalan and rATG followed by haplo-cord SCT in 45 patients with high-risk hematological malignancies. Thirteen patients (29%) belonged to ethnic or racial minorities, and almost half had AML. Median age was 50; weight 80 kg and twenty six (58%) had active disease at the time of transplant. The median CD34+ cell content post-selection of the haplo graft was 3.5 ×106/kg (25%–75% inter quartile range (IQR) 1.36–4.63). Minimal required UCB cell dose was 1×107 nucleated cells/kg. Median infused UCB total nucleated cell was 1.55×107 (range 1.24 to 2.09). 36 pts (80%) had at least a 5/6 matched UCB. The cumulative incidence of neutrophil recovery at day +50 was 95% (95% CI, 87–100%) with a median time to engraftment of 11 days (IQR 9 –15 days). The cumulative incidence of platelet recovery at day +100 was 83% (95% CI, 69–97%) with median time to platelet engraftment of 19 days (IQR 15–33 days). Patients received a median number of 12 platelet transfusions (IQR 6–22) and 7 red blood cell units (IQR 4–12) after the transplant. The median number of day of hospitalization during the first 100 days after transplant was 26 days (IQR 15–43 days). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB cells by 100 days. The median percentage of haploidentical cells in unfractionated peripheral blood was 86% on day 30, but declined to 22% by day 100, and to 2% by day 180. Conversely, the median percentage of cells of UCB origin increased from 10% by day 30, to 78% by day 100, and to 95% by day 180. There was also some re-emergence of host hematopoiesis over time. The percentage of day 100 haplo donor chimerism correlated closely with the CD34+ cell content of the haplo-identical graft (106/kg) (r=0.6225; P=0.0003). TNC, CD34+ cells, or CD3+ cells of the UCB did not correlate with cord donor chimerism. The cumulative incidence of acute GVHD (Grade II -IV) was 25% (95% CI 11–39). There were only two patients with chronic GVHD for a cumulative incidence of 6% at 1 year. Cumulative incidence of treatment related mortality was 9% (95% CI 1–17) at day 100 and 28% (95% CI 13–43) at one year. Cumulative incidence of disease recurrence was 11% (95% CI 3–19) at day 100 and 30% (95% CI 14–44) at one year. With a median follow up for survivors of 330 days (range 64–1259), estimated one year survival was 55% (95% CI 39–71) and progression free survival was 42% (95% CI 25–79). Active disease at the time of haplo-cord SCT tended to impair PFS, but this difference did not reach statistical significance (P=0.06). The cumulative incidence of CMV viremia was 42% (95% CI 26–58), but there were only four cases of CMV disease. The cumulative incidence of EBV viremia was 42% (95% CI 26–58%), but most cases were self limited or transient. Five patients developed biopsy or radiological proven PTLD, for a cumulative incidence of 11% (95% CI 0–22). RIC and haplo-cord transplant results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic GVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay and promising long term outcomes. UCB cell dose has no impact on time to hematopoietic recovery and UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. Disclosures: Off Label Use: Velcade in T-cell and aggressive non-MCL B-cell NHL.

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Synergy of Unrelated Donor and Full Intensity Conditioning Breaks the Control of Graft Versus Host Disease By Alemtuzumab

Blood ◽

10.1182/blood.v124.21.1206.1206 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1206-1206

Author(s):

Olivia Laverick ◽

Amy Publicover ◽

Laura Jardine ◽

Kile Green ◽

Alan Potter ◽

...

Keyword(s):

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Depletion ◽

Reduced Intensity Conditioning ◽

T Cell Depletion ◽

Gvhd Prophylaxis ◽

Full Intensity ◽

Conditioning Intensity ◽

Reduced Intensity

Abstract Many variables influence the risk of graft versus host disease following hematopoietic stem cell transplantation. Comparison between preparative regimens is hampered by the use of many different combinations of chemotherapy and radiotherapy, varying intensity of conditioning, use of T cell depletion and donors who are either siblings or unrelated volunteers. Many reduced intensity regimens also incorporate enhanced GVHD prophylaxis with in vivo T cell depletion. Here we describe a cohort of patients prepared in a modular fashion with either reduced or full intensity conditioning combined with a uniform GVHD prophylaxis regimen for all transplants with sibling donors (alemtuzumab 30mg) and for all with unrelated donors (UD; alemtuzumab 60mg). Thus it was possible to dissect independently the effect of conditioning intensity and sibling or UD type upon GVHD risk in this settig of in vivo T cell depletion. Patients and analysis: the study was a retrospective analysis of 258 sequential transplants performed in adults with hematological malignancy between September 2005 and September 2013 at a single UK institution. Reduced intensity conditioning (n = 221) included fludarabine 150mg/m2 plus melphalan 140mg/m2 or fludarabine 150mg/m2 plus busulfan 9.6mg/kg. Full intensity transplants (n = 37) received 12Gy TBI plus melphalan 140mg/m2, 12Gy TBI plus cyclophosphamide 120mg/kg, or busulfan 16mg/kg plus cyclophosphamide 120mg/kg. All patients with sibling donors received 30mg alemtuzumab and those with UD received a 60mg of alemtuzumab. UD matching was similar in both reduced intensity and full intensity cohorts (92.2% and 86.5% 10/10 matches, respectively) but patients receiving reduced intensity were older than those receiving full intensity conditioning (median age 51 vs 31; p < 0.001). Outcome was analyzed according to EBMT guidelines. Relapse, non-relapse mortality and cGVHD were treated as competing risks and analysed as cumulative incidence. Outcome: the incidence of acute GVHD grades I-IV was comparable between reduced intensity and full intensity sibling transplants (45% vs 45%; p = NS) indicating a lack of effect of conditioning intensity upon GVHD risk in this setting. There was a slight increase in the risk of GVHD between reduced intensity UD compared with reduced intensity sibling donor transplants (57% vs 45%; p = NS) but a marked synergistic increase between UD transplants performed with full intensity compared with reduced intensity conditioning (100% vs 57%; p = < 0.001). The incidence of grades III-IV acute GVHD was also higher in full intensity UD transplants (16%) compared with reduced intensity UD transplants (5%). The incidence of chronic GVHD was also highest in full intensity UD transplants but both conditioning intensity and UD contributed in an additive manner: the rate of chronic GVHD progressed from 33% to 44% in reduced intensity and full intensity sibling transplants respectively and from 57% to 75% for reduced and full intensity UD transplants, respectively. Two year overall survival was comparable in all groups, ranging from 55% to 70%. In keeping with the higher rates of acute GVHD in full intensity transplants performed with UD, this group experienced the lowest relapse risk (15% vs 29% for all the other groups combined; p = 0.04) but the highest non-relapse mortality, reaching 41% at 2 years compared with 28% for all the other groups combined (p = 0.08). Conclusion: these results show that alemtuzumab provides good protection from acute GVHD in reduced intensity transplantation from sibling and UD. In sibling transplants given identical GVHD prophylaxis, full intensity conditioning does not increase the risk of GVHD. In contrast, a slight increase in GVHD risk with UD transplants seen with reduced intensity conditioning, is amplified in a synergistic manner by full intensity conditioning. This is associated with a high non-relapse mortality, even though the median age of full intensity patients is more than 20 years younger than those receiving reduced intensity conditioning. Disclosures No relevant conflicts of interest to declare.

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Important Prognostic Impact of Early Monocytes Recovery after Reduced Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults

Blood ◽

10.1182/blood.v124.21.5923.5923 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5923-5923

Author(s):

Amandine Le Bourgeois ◽

Thierry Guillaume ◽

Jacques Delaunay ◽

Pierre Peterlin ◽

Viviane Dubruille ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Older Age ◽

Reduced Intensity Conditioning ◽

The Impact ◽

Reduced Intensity ◽

Grade Iii

Abstract Introduction: Little is known regarding the impact of hematopoietic and immune recoveries after double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT), especially after the TCF (low dose 2 Grays total body irradiation + cyclophosphamide 50 mg/Kg 1 day + fludarabine 200 mg/m² 5 days) reduced-intensity conditioning (RIC) regimen, which is considered as a standard RIC regimen for dUCB allo-SCT in adults Patients and Methods: Here we considered a homogeneous cohort of 47 patients (males: n=24; median age: 55.5 years (range: 17.5-69) who engrafted after a dUCB TCF allo-SCT performed between November 2006 and April 2013 in our department. Fifty-three percent of the patients had myeloid disease. The majority of cases were in complete remission at time of transplant (72.3%). GVHD prophylaxis consisted of cyclosporine + mycophenolate mofetyl in all cases. All patients received G-CSF from day 1 until neutrophils recovery. The median nucleated cells dose infused was 4.17 107/kg. The aim of the study was to investigate the impact on outcomes of the recovery of the following cellular subsets: leucocytes, monocytes, lymphocytes, neutrophils at day +30 and day +42, and CD4+, CD8+ T cells, B and NK cells at day+100. Results: Median times for neutrophils and platelets recoveries were 17 days (range: 6-59) and 37 days (range: 0-164), respectively. With a median follow-up of 30.4 months (range: 2.8-77.5), the 3-year overall and relapse-free survivals (OS, RFS), relapse incidence (RI), and non-relapse mortality (NRM) were 65.7%, 57.2%, 27.1% and 19%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 38.3% and 10.6%, respectively, while, 3-year incidence of chronic GVHD was 53.5% (limited 42%, extensive 11.5%). In univariate analysis, 3-year OS was significantly higher in case of lymphoid disease (80.9% vs 51.9%, p=0.05) or when achieving at day+30 or day +42 higher counts of leucocytes (> median: 2760/mm3; 79% vs 51%, p=0.05; median > 4250/mm3; 78.6% vs 55.4%, p=0.04) or monocytes (> median: 615/mm3; 87.5% vs 45.8 %, p=0.02; median > 830/mm3, 86.2% vs 54.1%, p=0.03). Older age (>median: 55 years) and higher monocytes count at day +42 (> median: 830/mm3) were significantly associated with higher 3-year RFS (63.6% vs 49.1 %, p=0.046; and 75.7 vs 44.4%, p=0.014). Higher leucocytes count at day +42 (>median: 4250/mm3) was the only factor associated with significant 3-year lower NRM (7.1% vs 31.7%, p=0.04), while younger age was associated with higher risk of grade 3-4 acute GVHD (16.7% vs 4.4 %, p=0.05). No factor was predictive of chronic GVHD in this series. In multivariate analysis, older age and early higher monocytes count after transplant were the two independent factors associated with a significantly higher OS (>55 years, HR: 0.21; 95%CI: 0.05-0.85, p=0.028; >615/mm3 at day +30, HR: 0.05; 95%CI: 0.01-0.43, p=0.006) while only older age remained independently associated with better RFS (>55 years, HR: 0.25, 95%CI: 0.08-0.78, p=0.017). No factor was predictive of NRM, grade 2-4 GVHD, grade III-IV acute or chronic GVHD. Conclusion: These results suggest that higher early monocytes recovery is predictive of outcome after dUCB TCF RIC allo-SCT in adults. Immune recovery seems to have no impact on survivals in this series while influence of age has to be confirmed by other studies. Our results pave the way for future studies aiming to closely and prospectively monitor the kinetics of hematopoietic and immune recoveries after this type of graft. As all patients received G-CSF after transplant, other immunostimulatory cytokines should be tested to ensure sufficient hematopoietic recovery in the setting of adult dUCB TCF RIC allo-SCT. Disclosures No relevant conflicts of interest to declare.

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No Influence of Peripheral Blood CD34+ and CD3+ Graft Cell Counts on Outcomes after Reduced-Intensity Conditioning Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2018-99-112453 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4577-4577

Author(s):

Alice Garnier ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

Amandine Le Bourgeois ◽

Alix Duquesne ◽

...

Keyword(s):

Board Of Directors ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Cell Content ◽

Post Transplant ◽

Cell Counts ◽

Gvhd Prophylaxis ◽

Reduced Intensity

Abstract Introduction Although associated with a higher incidence of acute GVHD, peripheral blood stem cells (PBSC) are increasingly used for haploidentical allogeneic transplantation with post-transplant cyclophosphamide (PTCY). Data reporting whether or not the composition of the PBSC graft impacts outcomes of patients receiving PTCY are still scarce. Materials and Methods This retrospective study included all adults allografted in our department who received a PBSC allotransplant after reduced-intensity conditioning (RIC) with PTCY. Grafts originated from a matched or haploidentical donor and recipients received a Baltimore-based or a Clo-Baltimore (where fludarabine is replaced by clofarabine)-based RIC regimen. All patients received cyclosporine + mycophenolate mofetyl and PTCY as GVHD prophylaxis. CD34+ and CD3+ graft cell contents were considered to study their potential impact on the following outcomes: OS, DFS, GRFS, acute grade 2-4 and 3-4 GHVD and chronic GVHD, early immune reconstitution (IR, lymphocytes and monocytes counts at days+30 and +100 post-transplant, CD4+, CD8+, NK and B cells at day+100 post-transplant). Results Between November 2013 and May 2017, 77 patients met the inclusion criteria. There were 48 males and 29 females with a median age of 58 years (range: 22-71) and a median follow-up for alive patients of 29.2 months (range: 8.4-53.2). Initial diagnoses were mainly acute myeloid (n=21) or lymphoid (n=6) leukemia, lymphoma (n=13), myelodysplastic syndrome (SMD, n=12), myelofibrosis (n=9). Thirty-eight patients were in complete remission at time of transplant (CR1 n=23; CR2 n=12, CR3 n=3) while 22 had active disease and 17 were in partial remission. Donors were sibling in 6 cases, matched unrelated (MUD) in 14, 9/10 mismatched unrelated in 1 and haploidentical in 56. Forty patients received a Baltimore RIC regimen and 37 a Clo-Baltimore RIC regimen. Analyses were performed in July 2018. Median infused CD34+ and CD3+ graft cell counts, based on recipients' weight, were 7.8 106/Kg (range: 1.45-14.24) and 22.23 107/kg (range: 1.95-66.75), respectively. All patients but three engrafted, the latter being 1 patient transplanted with a haplodonor, 1 with a MUD and 1 who died of infection during induction. Two-year OS, DFS and GRFS were 62.6% (52-74), 51.5% (40-63) and 36.6% (27-49), respectively. The incidences of grade 2-4 and 3-4 acute GVHD were 46.7% and 14.2%, respectively, while the incidence of moderate + severe chronic GVHD was 14%. Relapse occurred in 26 patients and non-relapse mortality (NRM) was 15.5%. Baltimore vs Clo-Baltimore patients shared similar median infused CD34+ and CD3+ graft cell counts and outcomes. The same was observed for patients allografted with a haplodonor or not, except for the incidence of grade 2-4 acute GVHD which was significantly higher for the haplo group at 57.1% vs 19% (p=0.006). This difference was first attributed to the higher CD3+ cell content infused in this group (median: 24.05 vs 18.85 107/kg, p=0.04). However, using the median of CD3+ cell graft content as threshold, the incidence of acute grade 2-4 GVHD was not different between low vs high groups when considering haplo patients. This suggests that it was rather the type of donor that did influence acute GVHD occurrence and that PTCY is of particular interest for GVHD prophylaxis when using matched donors. Partitioning the patients according to the median level of CD34+ cells, there was no difference in terms of 2-year OS (57.1% vs 60.7%, p=0.53), DFS (44.5% vs 55.6%, p=0.47) , GRFS (31.7% vs 44.3%, p=0.32), acute grade 2-4 (59% vs 39%, p=0.13) and 3-4 GVHD (17% vs 6.4%, p=0.29), and moderate + severe chronic GVHD (19.5% vs 20%, p=0.57). Similarly, partitioning patients according to median graft CD3+ cell content, outcomes were similar for 2-year OS (64.8% vs 55.8%,p=0.45), DFS (46.3% vs 55.8%, p=0.62), GRFS (36.3% vs 40.4%, p=0.63), acute grade 2-4 (44.7% vs 56.4%, p=0.42) and 3-4 GVHD (10.5% vs 15.3%, p=0.76), and moderate + severe chronic GVHD (14% vs 17.6%, p=0.91). Finally, early IR was not influenced by CD34+ and CD3+ graft cell contents. Conclusion: PBSC CD34+ and CD3+ graft cell contents have no impact on survivals, GVHD incidence nor early IR after a RIC allotransplant using PTCY as GVHD prophylaxis. As a consequence, there is no need to manipulate the graft nor cap the stem cells dose to be infused. These data have to be confirmed prospectively on a larger cohort of patients. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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