A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes

Abstract Abstract 496 HCT may provide long-term disease control for patients (pts) with relapsed and/or refractory acute leukemias (AL) and advanced myelodysplastic syndromes (MDS). Active disease burden at HCT is associated with high relapse rates and poor long-term outcomes. We hypothesized tolerable intensification would be achieved safely by clofarabine cytoreduction followed by HCT conditioning at the nadir and would result in improved outcomes. We performed a prospective study (3/08 – 9/10) to examine the feasibility and efficacy of clofarabine (Clo) cytoreduction prior to HCT for relapsed or refractory AL and MDS with > 5% marrow blasts. Clo was administered at 30mg/m2/day IV over 2 hours for 5 consecutive days. On Day 12 post Clo initiation, a bone marrow (BM) biopsy determined cytoreduction, followed by HCT conditioning by day 21 post-Clo. Our primary endpoint was to assess the proportion of pts who achieved effective cytoreduction, defined as BM cellularity <20% and BM blasts<10% on Day 12 post Clo initiation. Our secondary endpoints included (a) the proportion of pts able to proceed to HCT within 21 days of initiating Clo bridge, (b) Clo-related toxicities, and (c) disease free (DFS) and overall survival (OS) on Day 100 post HCT. 29 pts were enrolled and evaluable; 11 AML, 7 MDS, 3 t-MN, 4 secondary AML, 2 CML, 2 ALL; median age was 51 years (range 23–69); sex: 16 M, 13 F. 16 pts had high risk and 13 had intermediate risk cytogenetic profiles. 3 of 12 pts evaluated showed a FLT3 ITD mutation. 18 of 23 evaluable pts had high C-reactive protein levels at study entry (>5mg/L). All pts had ECOG performance status of 0 to 1. The median Charlson co-morbidity index was 1 (range 0–8). Effective cytoreduction was achieved in 15/29 pts (52%). Clo bridge therapy was well tolerated with mild toxicities (CTCAE v.3) prior to HCT as follows: 7% with grade (gr.) 1 creatinine elevation; 46% gr.1–2 and 7% gr.3 bilirubin elevation; 50% gr.1–2 and 25% gr.3 SGOT elevation, which were reversible. There were no hand-foot syndrome, cardiac, or CNS toxicities. All 29 pts (100%) successfully proceeded to HCT conditioning after clofarabine bridge – one pt with refractory AML, who achieved cytoreduction and conditioning, died one day before HCT due to sepsis. Median time from Clo initiation to HCT was 21 days (range 18–77). Two pts were delayed due to infection and/or failure to cytoreduce; both received second bridge with HiDAC mitoxantrone and achieved cytoreduction followed by HCT. 25 of 29 underwent reduced intensity conditioning (flu-mel-campath-17, clo-mel-campath 3, flu-mel-atg 5) and 26 of 28 received T-cell depletion (campath 22, ATG 5). Among the 28 transplanted pts, graft sources included: 23 PBSC (11 matched related, 12 matched unrelated), and 5 haploidentical PBSC plus a cord blood unit. With a median follow up 343 days after HCT, the median PFS = 353 days (95% CI 229–573) and the median OS = 381 days (95% CI 229–649). One year PFS is 65% by Kaplan-Meier estimate for cytoreduced pts compared to 33% in non-cytoreduced pts. Of the 28 pts who received transplant, 3 pts died before Day 100 – one due to sepsis before Day 28 post HCT, and two due to disease progression. At Day 28 post HCT, 26/27 pts (96%) had BM biopsies showing no evidence of residual disease – one pt had residual AML. The cumulative incidence of gr.2–3 acute GVHD by Day 100 was 9/27 pts, and 2/25 pts developed mild or moderate chronic GVHD within the first year. The Kaplan Meier estimate for one year survival is 65% (95% CI 35–84%) for the cytoreduced pt group and 41% (95% CI 16–65%) for the non-cytoreduced pt group. In summary, clofarabine bridge achieved cytoreduction in 52% of very high risk pts with advanced hematologic malignancies with low toxicity. Cytoreduction was associated with prolonged PFS, but late relapse remains problematic. Despite RIC and T-cell depletion, most pts achieved remission post-HCT with low rates of acute and chronic GVHD. This bridging approach provides a platform for testing novel post-transplant interventions. Disclosures: Off Label Use: Clofarabine is being used for treatment of advanced leukemia for cytoreduction prior to HCT. Locke:Genzyme: Honoraria. van Besien:Genzyme: Research Funding. Odenike:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Genzyme: Research Funding.

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Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML): Low Incidence of Relapse and Graft Versus Host Disease (GVHD) in Patients (pts) Transplanted without Active Leukemia Using in-Vivo T-Cell Depletion with Rabbit Anti-Thymocyte Globulin (r-ATG)

Blood ◽

10.1182/blood.v118.21.4527.4527 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4527-4527

Author(s):

James L. Slack ◽

Jose F. Leis ◽

Craig B. Reeder ◽

Joseph R. Mikhael ◽

Raoul Tibes ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Depletion ◽

T Cell Depletion

Abstract Abstract 4527 Introduction: The prognosis for pts with intermediate or high risk AML remains dismal, with relapse rates typically in the 60–80% range after treatment with chemotherapy alone. While allo-SCT can decrease the risk of relapse to 10–20%, widespread use of this modality is limited by relatively high rates of non-relapse mortality (NRM), often due to severe acute and/or chronic GVHD. Attenuation of severe GVHD, without a concomitant increase in relapse or NRM, should improve outcomes and result in cure of a larger fraction of AML pts. We therefore investigated the use of in-vivo T-cell depletion with r-ATG in pts with intermediate- or high-risk AML but without active leukemia at the time of allo-SCT. Patients and Methods: Pts (n = 43) were included in this retrospective analysis if they were between 18 and 65 years of age and had no evidence of active AML at the time of allo-SCT (see Table). All pts had 1 or more high-risk features: 1) adverse or intermediate risk cytogenetics (without NPM1 mutation if cytogenetically normal); 2) therapy-related or secondary AML; 3) high WBC count at diagnosis; 4) failure to achieve CR after 1 cycle of induction; or 5) not in CR1 at allo-SCT. Among the 43 pts, 10 received grafts from related donors, 14 from 10/10 matched unrelated donors (URDs), and 19 from mismatched URDs (9/10, n = 11; 8/10, n = 8). All pts received r-ATG according to institutional standard operating policy, with doses ranging from 2.5 – 10 mg/kg depending on donor type and degree of mismatch. All transplants were performed using PBSC. Additional GVHD prophylaxis included tacrolimus plus either methotrexate or mycophenolate mofetil. Results: The median age was 47 (range 20 – 65), and median follow-up for surviving pts is 12 (range 1 – 66) months. As of 8/5/11, 39 pts were alive, and 4 had died from multiorgan failure (n = 1), relapse (n = 1), GVHD (n = 1), and veno-occlusive disease (n = 1). The 2-year estimate of PFS is 84.7% (Fig. 1). The 2-year cumulative incidence of relapse is 6.8% (2 pts, days 97 and 147), and of non-relapse mortality 9.4%. Three pts developed severe (grades III-IV) acute GVHD by day 100 (cumulative incidence 4.6% at day 100) with no additional cases of severe acute GVHD beyond day 100. To date, 4 pts have developed moderate/severe chronic GVHD (cumulative incidence 16.8% at 2 yrs), with one death at day 344 related to complications of acute and chronic GVHD. CMV reactivation occurred in 29 pts (56%), with no deaths related to CMV. Three pts have reactivated EBV, with one case of PTLD (all treated with Rituximab). Conclusions: In this retrospective analysis of single center data, the inclusion of r-ATG in the GVHD prophylactic strategy appeared to significantly attenuate the incidence and severity of both acute and chronic GVHD. Although follow-up is relatively early, the incidence of relapse and NRM does not appear to be increased compared to contemporaneous pts treated without ATG. Given that almost half of the pts received grafts from mismatched URDs, this abrogation in risk of GVHD is significant and clinically relevant. While randomized studies are needed, these data suggest that in-vivo T-cell depletion with r-ATG ameliorates severe GVHD, without increasing relapse or non-relapse mortality, in AML pts without overt leukemia at the time of allo-SCT. Using this strategy, cure rates of 70 – 80% may be realistic and attainable for younger (</= age 65) AML patients who achieve a leukemia-free state and who have a reasonably matched related or unrelated donor. Disclosures: Reeder: Celgene: Research Funding; Millennium Pharmaceuticals Inc.: Research Funding; Novartis: Research Funding.

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Long Term Outcomes of Patients with Aggressive T-Cell Non-Hodgkin Lymphoma Undergoing Allogeneic Stem Cell Transplantation: Retrospective Results from a Single Center

Blood ◽

10.1182/blood-2019-131357 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4623-4623

Author(s):

Amandeep Salhotra ◽

Liana Nikolaenko ◽

Lu Chen ◽

NI-Chun Tsai ◽

Diane Lynne Smith ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

T Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Chronic Gvhd ◽

T Cell Lymphoma ◽

Long Term Follow Up

Background: Mature T cell and NK cell neoplasms collectively known as peripheral T-cell lymphomas (PTCL) comprise 15-20% of Non-Hodgkin lymphomas in adults and have a poor prognosis with a 5-year survival of less than 30% for the most aggressive subtypes. Allogeneic HCT (allo-HCT) is offered to eligible patients as a potentially curative modality in the salvage setting or in high risk patients to consolidate an initial response to frontline therapy. There are few studies that report clinical outcomes derived from large sample size and long-term follow up data. Methods: We retrospectively reviewed medical records of 87 consecutive patients with PTCL including transformed mycosis fungoides and NK/T-cell lymphoma without prior autologous transplant who underwent allo-HCT at City of Hope from January 2000 to June 2018 after IRB approval was obtained. Descriptive statistics were used to summarize baseline patient demographic, treatment, and disease characteristics. Kaplan-Meier curves and the log-rank test were used to evaluate the overall survival (OS) and progression-free survival (PFS). Cumulative incidences of time to relapse and time to non-relapse mortality (NRM) were calculated with relapse and NRM as competing risks. Cumulative incidences of acute and chronic GVHD were calculated as time to onset of GVHD with relapse and death as competing events for GVHD. Results: 87 patients were included for the analysis. Median age at the time of allo-HCT was 49 years (range 2-70 years). Histologies were PTCL-NOS (n=21); transformed CTCL (n=19); NK T-cell lymphoma (n=17); AITL (n=15), ALCL (n=7); gamma delta T-cell lymphoma (n=6) and other rare subtypes (n=2). None of the patients had a prior auto transplant. 42 patients (48%) received myeloablative conditioning, with the majority of patients receiving FTBI based conditioning (n=39) and three patients received BEAM regimen for conditioning. 45 patients (52%) received reduced intensity conditioning; fludarabine/melphalan based-conditioning was the most common regimen used (n=39). Sibling HCT was performed in 47 patients (54%), while MUD HCT was performed in 36 patients (41%) with fully matched HLA unrelated donor in 15 (17%) and HLA mismatched in 21 (24%) patients; 4 (5%) received haploidentical HCT. GVHD prophylaxis consisted of tacrolimus/sirolimus (n=54), tacrolimus/sirolimus/MTX (n=11), tacrolimus or cyclosporine/MTX (n=7), tacrolimus or cyclosporine/MMF (n=7), post-transplant cyclophosphamide/tacrolimus/MMF (n=5) and other (n=3). Source of stem cells was PBSC in 77 (88%), bone marrow in 5 (6%), and cord blood in 5 (6%) patients. At the time of allo-HCT, there were a total of 25 (29%) patients in complete remission (CR1 n=15, CR2+ n=10), 25 (29%) patients in partial remission 22 (25%) with induction failure and 14 (16%) with relapsed disease. The median follow-up among survivors was 6.9 years (range 1.1-15.5). The 5- and 10-year PFS was 47% (95% CI: 36%-58%) and 38% (95% CI: 26%-50%), respectively. The 5- and 10-year OS was 53% (95% CI: 41%-63%) and 42% (95% CI: 29%-54%), respectively (Fig.1). Relapses at 5 and 10 years were both 24% (95% CI: 16%-34%), while NRM at 5 and 10 years was 28% (95% CI: 19%-39%) and 37% (95% CI: 25%-50%), respectively. At day 100 after allo-HCT, the rates of acute GVHD grade II-IV were 41% (95% CI: 30%-51%) and grade III-IV of 16% (95%CI: 9%-25%). Chronic GVHD rates at 3 years were 62% (95% CI: 51%-72%), with extensive GVHD of 55% (95% CI: 44%-65%). On univariate analysis, age (> 60 or not), sex, TBI-based conditioning, donor type (MSD vs MUD), stem cell source or remission status prior to allo-HCT did not predict for overall survival in our study. Conclusions: Our results constitute the largest reported single-institution series with a long-term follow-up on allo-HCT outcomes in patients with aggressive T-cell NHL. The 5-year PFS and OS of 47 and 53%, respectively, are encouraging for the high-risk T-cell NHL patients with limited treatment options. Disclosures Salhotra: Celgene: Other: Research Support; Kadmon Corporation: Other: Non paid consultant. Popplewell:City of Hope: Employment. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Mei:Seattle Genetics, Inc.: Research Funding. Zain:spectrum: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau.

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Feasibility and Outcomes of T-Cell Depleted Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory AML and High Risk MDS

Blood ◽

10.1182/blood-2019-126211 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3324-3324

Author(s):

Satyajit Kosuri ◽

Sang Mee Lee ◽

Hongtao Liu ◽

Mylove Mortel ◽

Lucy A Godley ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees

Background: Survival in patients (pts) with relapsed/refractory (R/R) acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS) is dismal. Treatment options are limited; however, a proportion of these individuals can be rescued by allogeneic stem cell transplantation (allo-SCT). Historically, allo-SCT, especially for R/R myeloid diseases, has used myeloablative regimens and no T-cell depletion (TCD) to maximize graft-versus-leukemia effect, often restricting this approach to younger and fit pts with matched donors. The aim of this study was to investigate outcomes of in vivo T-cell depleted stem cell transplantation (TCD-SCT) in a high-risk AML and MDS population. Methods: We performed a retrospective analysis of 141 patients with R/R AML (n=108)/high risk MDS (RAEB or CMML, n=33) who received TCD-SCT at our center from 2002-2015. Median age was 55 years (18-71) with 37 (26%) pts older than 60. Patients underwent in vivo TCD with alemtuzumab or ATG and 117 (88%) received reduced-intensity conditioning (RIC). Alemtuzumab was generally given as 100 mg total divided over 5 days whereas rabbit ATG dosing included days -1, - 3, -5 (+/- on day -7). Alemtuzumab usually partnered with matched related (n=65; 46%) or unrelated (n=53; 38%) peripheral blood stem cell (PBSC) grafts whereas ATG mostly was a component of umbilical cord grafts combined with a CD34 selected haploidentical donor (haplo-cord) (n=23; 16%). Prognostic factors such as age, HCT-CI, CIBMTR score (Duval 2010), revised disease risk index (R-DRI), donor type and pre-transplant disease status were analyzed. Multivariate cox regression models were considered from forward selection for factors with a p value <0.1 in univariate analysis. Results: Table 1 summarizes baseline characteristics. Among the 141 R/R AML or high risk MDS pts, AML predominated (77%). Sixty six (47%) pts had primary induction failure (PIF), 42 (37%) had relapse and 33 (23%) had high risk MDS. Eighty three pts (59%) had peripheral blasts at time of TCD-SCT. Cumulative incidence (CI) of relapse for all pts was 53% and non-relapse mortality was 28% at 2 yrs. Two and 5 yr PFS rates for the group were 19% and 11%, respectively. Two and 5 yr OS rates for the group were 30% and 18%, respectively. Figure 1 shows OS by disease type. Day 100 mortality was 18%. Twenty one percent developed Grade 2-4 acute GVHD (aGVHD) (6% Grade 3-4), and only 5% developed chronic GVHD (cGVHD) requiring therapy. Figure 2 shows CI of cGVHD amongst disease types. Differences in 2yr survival outcomes were not significant among prognostic factors. Specifically, age 60+ vs younger was not prognostic (PFS 24% vs 17% p=0.4, OS 29% vs 29% p=0.7). Likewise, haplo-cord did not differ relative to matched donors in outcomes (PFS 18% vs 26% p=0.2, OS 35% vs 29% p=0.5). Conclusions: Although novel therapeutic approaches are emerging for R/R AML and high risk MDS, allo-SCT remains an established option for long-term disease control. In our analysis, outcomes after in vivo TCD-SCT in R/R AML and high-risk MDS pts treated with RIC mirror published historical results (Duval 2010, Schlenk 2010) but with low rates of cGVHD. The lack of significant difference in survival outcomes amongst age groups and donor sources suggests RIC with in vivo TCD can also be utilized as a platform in older individuals and those with alternative donors. With high relapse rates in this population, better pre-transplant disease reduction, minimal residual disease monitoring and post-transplant maintenance will be critical to increase long-term cures. Disclosures Liu: Agios: Honoraria; Arog: Other: PI of clinical trial; BMS: Research Funding; Karyopharm: Research Funding; Novartis: Other: PI of clinical trial. Larson:Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy; Celgene: Consultancy. Odenike:Oncotherapy: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Astex Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; Agios: Research Funding; CTI/Baxalta: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Kline:Merck: Honoraria; Merck: Research Funding. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Bishop:Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Artz:Miltenyi: Research Funding.

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Reduced-Intensity Conditioning (RIC) with Busulfan, Fludarabine and Campath-1H Is Complicated by a High Rate of Graft Failure and Severe Viral Complications in Patients with CLL.

Blood ◽

10.1182/blood.v104.11.5080.5080 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5080-5080 ◽

Cited By ~ 1

Author(s):

Johannes Schetelig ◽

Martin Bornhaeuser ◽

Christian Thiede ◽

Brigitte Mohr ◽

Uta Oelschlaegel ◽

...

Keyword(s):

T Cell ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unknown Etiology ◽

T Cell Depletion ◽

Hematopoietic Stem ◽

One Year

Abstract Recently we demonstrated that RIC with busulfan, fludarabine and ATG followed by allogeneic hematopoietic stem cell transplantation (HSCT) induced molecular remissions in patients (pts) with advanced CLL. However, this approach was hampered by severe GVHD. In an attempt to lower the rate of severe GVHD we replaced ATG by campath in a new study protocol. Patients and Methods: 20 pts with a median age of 54 years (range, 43 to 64) and advanced CLL were included. A median of 3 prior chemotherapy regimens had been given before HSCT, including fludarabine-containing regimens in all but two pts with autoimmune hemolysis. High risk cytogenetic features (17p−, 11q−, +12) were present in 9 pts. After conditioning with busulfan (8 mg/kg), fludarabine (150 mg/m2) and campath (75 mg) on days −9 to −5 peripheral blood stem cells from matched related (n=4) or unrelated donors (n=16) were transplanted. GVHD prophylaxis consisted of CSA monotherapy. Campath levels were analysed in frozen serum samples by BioAnaLab, Oxford, UK. Results: Two pts had no detectable campath level at the day of HSCT, while four pts had levels between 0.5 to 1.8 microgram/mL. Regeneration of neutrophils (>0.5/nl) and platelets (>20/nl) required a median of 17 (range, 14–25) and 10 (range, 0–27) days, respectively. Incomplete T-cell chimerism (<50%) was observed in 7 pts and subsequently 3 pts experienced secondary graft failure on days 134, 152 and 324. Six pts received donor lymphocyte infusions (DLI) for the conversion of incomplete T-cell chimerism (N=4) or progressive disease (N=2). Sponaneous acute GVHD II° to IV° occurred in 9/20 pts. After DLI four additional pts developed acute GVHD II° to IV°. Limited chronic GVHD occurred in 9 and extensive disease in 2 pts. In CMV seropositive pts the day 100 probability of CMV infection was 74% (95% CI, 44% to 100%). Severe encephalitis (HHV6, EBV and JC virus as suspected agents) was observed in 5 pts. Two pts recovered without sequelae, 2 pts are cognitively handicaped and one pt died. Hemorrhagic cystitis (CTC 2/3) occurred in 2 pts. After a median follow-up of 13 months (range, 6 – 26 months), 15 pts are alive. Four pts died from treatment related complications. Causes of death were pneumonia of unknown etiology (N=2), encephalitis (N=1) and GVHD grade IV (N=1). One pt died from severe acute GVHD subsequent to the treatment of relapse with DLI. One-year overall and progression-free survival was 75% (95% CI, 55% to 95%) and 50% (95% CI, 25% to 75%), respectively. The one-year probability of non-relapse mortality was 20% (95% CI, 2% to 38%). The number of binding sites for campath is highly variable in pts with progressive CLL resulting in interindividually highly variable pharmacokinetics. Differences in the extent of in vivo T-cell depletion might therefore explain the individually varying T-cell engraftment pattern. In addition, the high incidence of severe viral infections reflects impaired immunoreconstitution. Including pts after DLI we observed a substantial rate of severe GVHD. Based on these data we decided to skip the strategy of in vivo T-cell depletion with campath in patients with CLL.

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Long Term Outcomes of Unrelated Donor Bone Marrow Transplantation in Children with Severe Aplastic Anemia: An Update of the Milwaukee Experience.

Blood ◽

10.1182/blood.v108.11.3128.3128 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3128-3128

Author(s):

Julie-An Talano ◽

Bruce Camitta ◽

Carolyn Keever-Taylor ◽

Lynnette Anderson ◽

Caitlin Wallach ◽

...

Keyword(s):

T Cell ◽

Graft Rejection ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Musculoskeletal Problems

Abstract We demonstrated that partially T-cell depleted unrelated donor HSCT for Severe Aplastic Anemia (SAA) is a reasonable treatment option for children and young adults who fail immune suppression therapy. (Margolis et al., 1996, Br J Haematol.)We now report, long term follow up data for 40 patients transplanted for SAA between the years 1986 to 2002. The patient group consisted of 22 males and 18 females, ranging in age from 0.5–24.3 (median 8.5) yrs. Retrospective molecular HLA typing shows that donors were matched for nine patients, and mismatched for 31. Patients were conditioned with cytosine arabinoside, cyclophosphamide, and total body irradiation, as previously described. Some patients additionally received ATG to promote engraftment. The marrow product underwent partial T-cell depletion using an antibody and complement process as described. in the original report. GVHD prevention was with cyclosporine. Three patients did not engraft. All three with non-engraftment died within 60 days of BMT from infectious and hemorrhagic complications. Since employing ATG as part of the conditioning regimen, all patients have engrafted. Of the 37 patients who engrafted the median time to an ANC>500 was 16 (range 8–25) days. Eight patients developed Grade II AGvHD, 1 grade III and 2 grade IV. Of 29 evaluable patients, 12 developed limited chronic GVHD, and 3 developed extensive CGvHD. Twenty-one patients are currently surviving with a follow-up of 4 to 19 yrs. (median 12.7 yrs.). Overall survival is 52% at 12 yrs. Of the 19 patients that died, causes of death included infection n=7, (PCP n=1, CMV n=2, Aspergillus n=1, Adenovirus n=2, PTLD n=1); GVHD n=2; Graft failure n=3; Multiorgan system failure n=2; ARDS n=1; Hemorrhage n=2; VOD n=1; Secondary malignancy n=1 (Hodgkin’s disease n=1). Of the 21 surviving patients, all patients have a Karnofsky score ≥ 90%. The late effects in our survivors include two secondary malignancies (osteosarcoma and vaginal carcinoma in situ); cataracts n=11; growth retardation n=11; gonadal dysfunction n=6; hypothyroidism n=5; cognitive problems n=4; musculoskeletal problems (AVN, osteoporosis) n=7; hyperlipidemia n=3; and renal disease n=2. One patient had a subsequent pregnancy that resulted in a preterm delivery at 26 weeks and a neonatal death. Our experience, now with long follow-up, shows that an intensive conditioning regimen to prevent graft rejection, coupled with partial T-cell depletion of an unrelated donor bone marrow graft to decrease the risk of GVHD, provides for durable survival with an acceptable incidence of acute and chronic GVHD. The relatively low incidence of GVHD is notable in view of the number of patients with donors who had identified HLA disparity. However, there are long-term risks associated with this regimen including secondary malignancies, delayed growth and development, metabolic problems, and musculoskeletal problems. We are encouraged by the recently reported short-term results using regimens for this disease which avoid or limit the use of TBI. Recognizing that many patients have donors with HLA disparity, which increases the risks of graft rejection and GVHD, we believe that combining partial T cell depletion with advanced immunomagnetic methods of graft manipulation and a fludarabine based regimen may allow us to balance the risks of graft rejection, GVHD, and late-effects that are unique to patients with SAA.

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Donor CD34+ Cell Chimerism at Day 28 and Chronic Graft-Versus-Host Disease (GvHD) but Not High-Risk Cytogenetics Influence Outcome of Allogeneic Hematopoetic Cell Transplantation (HCT) Following Reduced Intensity Conditioning (RIC) in Patients with AML and MDS.

Blood ◽

10.1182/blood.v108.11.547.547 ◽

2006 ◽

Vol 108 (11) ◽

pp. 547-547 ◽

Cited By ~ 1

Author(s):

Haifa K. Al-Ali ◽

Claudia Nehring ◽

Rainer Krahl ◽

Cornelia Becker ◽

Sabine Leiblein ◽

...

Keyword(s):

Risk Factors ◽

T Cell ◽

High Risk ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Group I ◽

Cd34 Cells ◽

Patients At Risk ◽

Group Ii

Abstract HCT after RIC is used increasingly to treat older or infirm patients with AML or MDS. In the current analysis we looked for risk factors influencing outcome including cytogenetics, kinetics of donor CD34+ and T-cell chimerism (CC). Patients and methods: From July 1998 - December 2005, 119 consecutive patients [66 m/53 f; median age 60 (range 21–74) years] with AML (n=99; 83%) and high-risk MDS (n=20; 17%) were treated within the OSHO AML studies before HCT. Seventy (59%) of the patients had intermediate-risk cytogenetics and 44 (37%) high-risk cytogenetics. Patients were either in CR1 (n= 66; 55%), CR2 (n=18; 15%), >CR2 (n=28; 24%), or were untreated (n=7; 6%) at transplant. HCT was performed from matched related (n= 33; 28%) and matched unrelated (n= 86; 72%) donors after RIC (200cGy TBI + fludarabine 30 mg/m2/day on 3 consecutive days) and followed by immunosuppression with cyclosporine and mycophenolate mofetil. Marrow donor chimerism was determined in T-, and CD34+−cells at days (d) 28, 56, 84, and thereafter at 3 month intervals using either XY chromosome FISH in gender mismatched, or PCR based analysis of polymorphic micro satellite regions in gender matched HCT. Results: Engraftment was documented in 112 (94%) of the 119 patients. Survival (OS), disease free survival (DFS), relapse incidence (RI), and non-relapse mortality (NRM) of engrafted patients was 40%, 38%, 46%, and 30% at 3 years respectively. In multivariate analysis, only >90% donor CD34+ CC at d 28, chronic GvHD, and CR1, but not cytogenetic risk factors were associated with an improved OS and DFS. Patients with >90% donor CD34+ CC at d 28 (group I) had an OS of 50% compared to 9% in patients with donor CD34+ CC <90% (group II) (p=0.002). Accordingly, RI in group I was 35% compared to 85% in group II (p<0.0001). Again, donor CD34+ CC at d 28 but neither donor T-cell chimerism nor high-risk cytogenetics correlated with relapse. Relapse occurred in 41/109 (38%) patients at a median of 121 d. All patients (n=19) with haematological relapse within 100 days post transplant died despite reduction/withdrawal of immunosuppression. Of the 22 patients with later relapse, six went into permanent complete remission by reduction/withdrawal of immunosuppression. A decrease of CD34+ chimerism was detected in a further six patients and all responded to a decrease in immunosuppression. The incidence of acute (grades ≥ I) and chronic (limited and extensive) GvHD was 50%, and 55% respectively. OS was 10%, 46%, and 62% for patients with no GvHD (A), acute GvHD only (B), and chronic GvHD (C) (p=0.0001). DFS for A, B, C was 20%, 38%, and 55% respectively ((p=0.0001). RI was highest for A (72%) compared to B (49%) and C (25%) (p<0.0001). Conclusions: HCT after RIC offers long-term OS and DFS in AML/MDS even in patients with high-risk cytogenetics. CR1, donor CD34+ CC >90% at d 28 and chronic GvHD correlate with an improved outcome and decreased relapse incidence. Careful monitoring of donor CD34+ CC can identify patients at risk for relapse, thereby allowing early immunmodulation.

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Functionally Altered GPI-Anchor Negative Treg Following Alemtuzumab-Based T-Cell Depletion Are Associated with Acute Gvhd.

Blood ◽

10.1182/blood.v120.21.3059.3059 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3059-3059

Author(s):

Eva M Wagner ◽

Lukas A Schaefer ◽

Tobias Bopp ◽

Matthias Theobald ◽

Wolfgang Herr ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Depletion ◽

Gpi Anchor ◽

Activation Markers ◽

T Cell Depletion ◽

Hematopoietic Stem

Abstract Abstract 3059 Introduction: The monoclonal anti-CD52antibody Alemtuzumab is frequently used for T-cell depletion (TCD) in the context of allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft versus host disease (GVHD). We previously demonstrated the long term persistence of functionally impaired glycosylphosphatidylinositol (GPI)-anchor negative effector T-cells in patients receiving high dose (100mg) Alemtuzumab in combination with a dose reduced conditioning regimen (Fludarabin + Melpahlan) (Meyer, Wagner et al. BMT 2010). Despite of Alemtuzumab-mediated TCD, half of our patients developed acute GVHD. Since regulatory T cells (Treg) play a major role for controlling GVHD, we asked whether GPI-anchor negative Treg are present in patients with or without GVHD. Methods: We analyzed peripheral blood samples of 12 patients with acute GVHD (aGVHD), 7 patients with chronic GVHD (cGVHD), and 10 patients who never developed GVHD after Alemtuzumab-mediated TCD. To analyze Treg-subsets, we stained for CD3, CD4, CD25, CD127, FoxP3, CD52 as well as for the activation-markers GARP, HLA-DR and CD45RA. Treg were identified as CD3+CD4+CD25+CD127- or CD3+CD4+CD25+FoxP3+ cells and subdivided according to their CD52-expression. We used FLAER staining to confirm that the loss of CD52 on Treg resulted from the loss of the GPI-anchors themselves. We were able to study Treg subpopulations in the time course of patients who recovered from acute GVHD in comparison to patients with persisting late acute GVHD. In individual patients, we isolated GPI-anchor positive and negative Treg by FACS-Sort, expanded them and performed Treg suppression assays. Results: GPI-anchor negative Treg were observed in all patients, independent of the development of GVHD. However, the frequency of GPI-anchor negative Treg varied considerably between patients with acute GvHD and those with chronic GVHD or without GvHD. The percentage of GPI-anchor negative Treg was significantly elevated in patients with aGVHD: median 80.35% (range 56,2–96,8%) in comparison to 17,4% (range 0–57,8%) in patients with cGVHD or without GVHD. Activated Treg were almost exclusively detected among GPI-anchor positive Treg-subpopulation. Patients who resolved from aGVHD restored GPI-anchor positive Treg and the amount of activated Treg rose. The percentage of GPI-anchor negative Treg populations remained high in patients with ongoing aGVHD. In addition, these patients had no GARP-positive activated Treg even under long term immunosuppressive treatment. Preliminary experiments with sorted and expanded Treg populations suggest that GPI-anchor negative Treg were unable to suppress T-cell proliferation upon IL-2 stimulation. Summary: We demonstrate for the first time the reconstitution of GPI-anchor negative Treg in patients following Alemtuzumab-mediated TCD. These T cells were functionally altered and were less likely to exhibit an activated phenotype in vivo. Ongoing acute GVHD was associated with high percentages of GPI-negative Treg suggesting that their functional alteration might play a role in aGVHD pathophysiology. This is in line with the finding that only in patients who resolved aGVHD, the frequency of GPI-anchor positive Treg increased significantly. Further functional analyses are ongoing to estimate the cellular consequence of missing GPI-anchored proteins. In addition, correlating the reconstitution of GPI-anchor negative T-cell populations with further clinical events is ongoing. Disclosures: No relevant conflicts of interest to declare.

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Post-Transplant Cyclophosphamide and Sirolimus in Matched Related and Unrelated Allogeneic Transplant with a Treosulfan-Based Conditioning

Blood ◽

10.1182/blood-2018-99-111352 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4662-4662

Author(s):

Jacopo Peccatori ◽

Serena Albanese ◽

Raffaella Greco ◽

Francesca Lorentino ◽

Fabio Giglio ◽

...

Keyword(s):

High Risk ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Free Survival ◽

Allogeneic Hsct ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Introduction: Post transplant cyclophosphamide (PT-Cy) has recently emerged as a very promising pharmacological strategy to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical hematopoietic cell transplant (HCT). We recently reported a promising preliminary experience on the use of PT-Cy and sirolimus as graft-versus-host disease (GVHD) prophylaxis in matched allo-HSCT (Greco R et al, Blood 2016). Herein we describe long-term outcomes of matched allogeneic HSCT, using treosulfan-based conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: In our center, we collected 104 adult patients (pts) receiving matched HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n=43). Donor was matched related (MRD) for 45 pts, 10/10 matched unrelated (MUD) for 39 pts and 9/10 MUD for 20 pts. Median age was 48 years (range 19-78). At HSCT, 51% of patients were not in complete remission (CR), 39% were in CR1 and 11% in subsequent CR. Graft source was mainly PBSCs (95%). All pts received a conditioning regimen based on treosulfan and fludarabine; 89% received an intensified conditioning with the addition of melphalan. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was added from day 5 to day 30, only in MUD. All patients were treated according to current institutional programs upon written informed consent for transplant procedures. Results: Median follow up was over 16 months (range 3-51). Median CD34+ and CD3+ cell doses were 5.6x10^6/Kg (range, 1.5-10.9) and 2.0x10^8/Kg (range, 0.2-8.0), respectively. All the recipients of allo-HSCT experienced a sustained donor cell engraftment. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 21% and 9%, respectively. The cumulative incidence of chronic GVHD was 25% at 2 years; we observed severe chronic GVHD only in 4% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were 33% and 8% at 2 years, respectively. Two-year overall survival (OS) was 67% and progression free survival (PFS) 59%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 52% at 2 years, in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death. There was a longer OS, 2-year OS was 77% (p = 0.05), and a trend towards higher PFS and GRFS, 63% (p=0.07) and 58% (p=0.06) respectively, for pts with CR status at HSCT. We did not found a significant effect of HLA-matching (9/10 versus 10/10) or donor type (related versus unrelated) on major transplant outcomes (NRM, PFS, GRFS, relapse, acute and chronic GvHD). Conclusion: These outcomes confirmed that matched allogeneic HSCT using treosulfan-based chemotherapy, PT-Cy and sirolimus, is associated with low NRM and acceptable severe GVHD, providing relevant long-term survival in high-risk diseases. A randomized trial comparing this strategy with other kind of in-vivo T-cell depletion (i.e. ATG) is warranted. Disclosures Vago: Moderna TX: Research Funding; GENDX: Research Funding.

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Proliferative and differentiative responses of B cells from human marrow graft recipients to T cell-derived factors

Blood ◽

10.1182/blood.v69.1.308.bloodjournal691308 ◽

1987 ◽

Vol 69 (1) ◽

pp. 308-315 ◽

Cited By ~ 1

Author(s):

K Matsue ◽

LG Lum ◽

RP Witherspoon ◽

R Storb

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Chronic Gvhd ◽

B Cell Activation ◽

Short Term ◽

Marrow Graft ◽

One Year

Upon activation, B cells express growth and differentiation receptors that permit them to proliferate and differentiate. The aim of this study is to define the nature of the intrinsic B cell defects found in marrow recipients using assays for B cell activation, proliferation, and differentiation. B cells from five short-term (less than three months postgrafting) and 15 long-term (greater than one year postgrafting) marrow recipients (ten with and five without chronic graft-v -host disease [GVHD]) were studied. T cell supernatants (T-sup) were prepared by stimulating normal T cells with 12–0-tetradecanoyl- phorbol-13-acetate (TPA) and phytohemagglutinin. Highly purified B cells were used to assess B cell proliferation responses to T-sup after Staphylococcus aureus Cowan I (SAC) activation and for B cell immunoglobulin production responses to T-sup stimulation after SAC activation. B cells from all five short-term patients and one long-term patient with chronic GVHD did not respond to any stimulation. B cells from two patients with chronic GVHD responded to SAC but had decreased proliferative and differentiative responses to T-sup. B cells from three of seven patients with chronic GVHD and two of five long-term healthy patients could proliferate but could not secrete immunoglobulin in response to SAC plus T-sup stimulation. Furthermore, there was a significant correlation between serum IgG and/or IgM in marrow recipients and the differentiative responses of their B cells to T-sup (P = 0.0075, Fisher's Exact). B cell defects occur at various stages of maturation postgrafting. These defects include the failure to respond to the SAC activation signal, the failure to proliferate in response to T-sup, and the failure to differentiate in response to T-sup. These findings are probably due to the inability of B cells from certain marrow recipients to undergo a second round of ontogeny.

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Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽

10.1182/blood.v128.22.3980.3980 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3980-3980

Author(s):

Jae-Ho Yoon ◽

Sung-Soo Park ◽

Young-Woo Jeon ◽

Sung-Eun Lee ◽

Byung-Sik Cho ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Median Time ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Advisory Committees

Abstract Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD. Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043). Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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