Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplant with in Vivo T-Cell Depletion By Alemtuzumab: Incidence, Outcome and Pattern of Organ Involvement

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3912-3912 ◽  
Author(s):  
Maria Chiara Finazzi ◽  
Cristina Boschini ◽  
Janice Ward ◽  
Charles Craddock ◽  
Alessandro Rambaldi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Organ Involvement ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
T Cell Depletion

Abstract Introduction Graft-versus-Host Disease (GvHD) is one of the leading causes of mortality and morbidity following allogeneic stem cell transplant. In vivo T cell depletion by alemtuzumab as part of the transplant conditioning is an effective strategy to reduce the risk of GvHD. While it is recognised that the overall incidence of GvHD is reduced by alemtuzumab, the incidence of chronic GvHD as defined by the National Institute of Health (NIH) consensus criteria, the impact on outcome, and the pattern of organ involvement have not been defined yet in this transplant setting. Methods Consecutive patients (n = 323) undergoing allogeneic stem cell transplantation at the Queen Elizabeth Hospital, Birmingham, between January 1 2008 and June 30 2012 were reviewed in this retrospective, single centre study. Medical records were examined and data regarding the development of GvHD were collected; NIH consensus criteria for diagnosis and staging of chronic GvHD were stringently applied. Clinical characteristics of GvHD occurring in patients transplanted following T cell depletion by alemtuzumab administration (n=248) were compared with those of patients transplanted with a T cell replete graft (n=75). Patients receiving alemtuzumab were mainly treated with reduced-intensity conditioning protocols, while patients in the no-T-cell depletion group were mainly treated with a myeloablative, sibling transplant. Results After a median follow up of 38.4 months, the cumulative incidence (CI) of grade II-IV classic acute GvHD was 35% and 48% for patients transplanted respectively with or without T cell depletion by alemtuzumab (p= 0.041, Figure 1); with a CI of grade III-IV classic acute GvHD of 13% and 27% (p=0.007). The 2-years CI of grade II-IV late acute GvHD was not significantly different in the two groups (20% and 23% for patients respectively treated with or without alemtuzumab, p=0.589, Figure 2). T cell depletion by alemtuzumab significantly reduces the 3 years cumulative incidence of classic chronic GvHD (5% versus 31%, p<0.0001, Figure 3.A), but without a significant difference in the incidence of overlap syndrome between patients with and without T cell depletion (3 years CI respectively 6% and 7%, p=0.839, Figure 3.B). The pattern of organ involvement by classic acute GvHD was similar in patients with and without T cell depletion. The pattern of organ involvement by late acute GvHD in the alemtuzumab group was, however, significantly different compared to the T cell replete group (skin-gut-liver involvement reported respectively in 83%-28%-4% of patients and 56%-48%-20% of patients, p=0.003). Distribution of organ involvement by classic chronic and overlap syndrome was similar in the two groups; however, it seems that alemtuzumab prevents the development of lung GvHD (lung GvHD developed in 4 patients over the 75 patients of the no-T-cell depletion group, while none of the 248 patients transplanted with alemtuzumab experienced lung GvHD). In a multivariate analysis, the development of chronic GvHD was an independent predictor of higher mortality risk (HR 1.66, p = 0.04) and severe NIH global score at peak was confirmed as a poor prognostic factor for survival (HR 2.27, p=0.02). The negative impact of chronic GvHD and of the severe forms of chronic GvHD was independent of age and alemtuzumab administration. Conclusion This retrospective analysis provides for the first time data on the incidence rates of NIH-defined GvHD categories in patients transplanted after T cell depletion by alemtuzumab. Patients transplanted with alemtuzumab experienced a lower incidence of classic acute and classic chronic GvHD compared to patients not receiving T cell depletion. In contrast, alemtuzumab conditioning appeared to have no effect on the incidence of late acute GvHD or overlap syndrome, suggesting that these two entities of GvHD are driven by different immunological mechanisms as compared to classic acute and classic chronic GvHD. We also confirmed the utility of the NIH classification of GvHD and of the NIH global severity score to predict survival in alemtuzumab-conditioned allogeneic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

Comparable Outcomes after Allogeneic Stem-Cell Transplantation with Intravenous Busulfan or Treosulfan-Based Reduced-Intensity and Reduced Toxicity Regimens in Acute Myeloid Leukemia. a Study on Behalf of the Acute Leukemia Working Party of EBMT

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2280-2280
Author(s):  
Avichai Shimoni ◽  
Myriam Labopin ◽  
Bipin N. Savani ◽  
Rose-Marie Hamladji ◽  
Dietrich W. Beelen ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Advanced Disease ◽  
Chronic Gvhd ◽  
Working Party ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Reduced Toxicity

Abstract Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). Myeloablative conditioning (MAC) is associated with prohibitive rates of non-relapse mortality (NRM) in older and less medically fit patients. Several reduced intensity conditioning regimens (RIC) and more recently the more dose-intensive reduced toxicity myeloablative (RTC) regimens were designed to replace MAC in this setting. The backbone of these regimens is usually fludarabine with busulfan and more recently also with treosulfan, but there is no clear data on the comparative outcomes with these different regimens in the different SCT settings. The current study included 3561 patients with AML given a first allogeneic SCT from an HLA-matched sibling (n=1683) or a 10/10 matched unrelated donor (n=1878) between the years 2000-2014 and reported to the acute leukemia working party (ALWP) of EBMT. Only patients given fludarabine with either intravenous busulfan (ivBu), (FB, n=2990) or treosulfan (FT, n=571) alone were analyzed. Fludarabine and ivBu at 6.4 mg/kg (n=1457) or treosulfan at 30-36 gr/m2 (n=168) were considered RIC regimens while fludarabine with ivBu at a total dose of 9.6-12.8 mg/kg (n=1533) or treosulfan at 42 gr/m2(n=403) were considered RTC regimens according to EBMT criteria. The median age of FB and FT recipients was 55.5 and 58.3 years, respectively (P< 0.0001). The status at SCT was 72.5% CR1, 15.0% CR2 and 12.5% advanced disease in the FB group compared to 55.0%, 20.3% and 24.7% in the FT group, respectively (P<0.0001). More FT recipients had SCT from unrelated donors (64.8% Vs. 50.4%, P<0.0001) but less had in-vivo T-cell depletion (58.4%Vs 70.5%, P<0.0001). Cytogenetic subgroup distribution was similar between the groups. Ninety percent had peripheral blood stem cell grafts in both groups. The median follow-up was 19 and 43 months after FB and FT, respectively. Using univariant analysis, the 2-year relapse incidence (RI) was 32.7% and 35.5%, respectively (P=0.49). NRM was 17.6% and 19.4%, respectively (P=0.09). Leukemia-free survival (LFS) and overall survival (OS) were 49.5% and 54.8% after FB and 45.1% and 52.6% after FT, respectively (P=0.04, P=0.17). Acute GVHD grade II-IV and chronic GVHD were 23.1% and 35.7% after FB and 18.8% and 39.8% after FT, respectively (P=0.03, P=0.04). In all, the GVHD/ relapse-free survival (GRFS) was 36.5% and 31.5%, respectively (P=0.08). After adjusting for the differences in patient characteristics, there was no difference between the FB and FT groups in RI, NRM, LFS, OS and GRFS. However, acute GVHD grade (II-IV) was higher after FB (HR, 1.49, P=0.0004). The same observations were seen when the analysis was limited to RIC or RTC regimens only, or when only patients in remission were analyzed. However, when analyzing only the 516 patients with advanced disease at SCT, 2-year OS was 29.7% and 43.0% after FB and FT (P=0.002) and this difference remained significant in the multivariant analysis (HR, 1.50, p=0.003). Among the entire group, the factors associated with reduced survival were advanced age (HR 1.01, P<0.0001), secondary AML (HR 1.19, P=0.005), CR2 (HR 1.21, P=0.007) and advanced disease (HR 2.02, P<0.0001) compared to CR1, and female donor to male recipient (HR 1.15, P=0.03). Conditioning type and intensity, donor type, CMV status and in vivo T-cell depletion were not significant. Relapse was lower and NRM was higher with RTC compared with RIC, but OS was similar. The same factors predicted for GRFS, a surrogate for quality of life, with the only difference been the positive role of in vivo T-cell depletion (HR 0.8, P=0.0002). In conclusion, RIC and RTC regimens with ivBu or treosulfan-based regimens are associated with similar transplantation outcomes. OS is primarily affected by disease factors such as status of disease at SCT and secondary leukemia. Treosulfan- based conditioning is associated with a lower rate of acute GVHD, but with similar rates of chronic GVHD, NRM and GRFS. Treosulfan conditioning may have some advantage in patients with advanced disease at SCT. Disclosures No relevant conflicts of interest to declare.

T-Cell Depleted PBSCT Mitigates Acute GVHD, but Preserves Protective Chronic GVHD. Long Term Follow up of 138 Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 140-140
Author(s):  
Aldemar Montero ◽  
Bipin N. Savani ◽  
Stephan Mielke ◽  
Scott R. Solomon ◽  
Richard Childs ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Cell Transplant ◽  
T Cell Depletion ◽  
Transplant Outcome ◽  
Standard Risk

Abstract Between 1997 and 2004, 138 patients with hematological malignancies had an HLA-identical sibling peripheral blood stem cell transplant (PBSCT). Preparative regimen was TBI (12–13.6Gy), cyclophosphamide 120mg/kg +/− fludarabine 125mg/m2. T-cell dose was adjusted to 0.2-1 x 105 CD3+ cells/kg. CD34 dose was 2.7 – 15.9 x 106/kg (median 5.9). Patients without ≥ grade 2 acute GVHD received 1 or 2 donor lymphocyte infusions (DLI) of 107 CD3+ cells/kg between days 45 and 100. For GVHD prophylaxis, all patients received cyclosporine (CSA) following the DLI for a minimum of 6 months. In addition 72 patients received CSA in the first 6 weeks post PBSCT and 66 received no CSA immediately post-transplant. Patients were aged between 10–56 (median 34 years). Seventy-seven patients with CML-CP (42), acute leukemia in first remission (22) or MDS RA (10) were designated as standard risk (SR) for transplant outcome. Sixty-one patients with more advance or refractory disease were designated as high risk (HR) for transplant outcome. Seven patients, distributed in both groups had CLL, NHL, MM and CMML. Overall survival, relapse and TRM were 58 ± 4.5%, 40.2 ± 5.5% and 18.4 ± 3.4% respectively after a median follow up of 4 years. Twenty-two patients did not receive DLI, 70 received one and 46 received two DLI. Twenty-three patients had TRM, 2 from graft failure, 5 from acute or chronic GVHD. Fifty two (37%) developed ≥ grade II, and 21 (15%) patients grade III-IV acute GVHD. Forty two (30%) had limited and 30 (22%) extensive chronic GVHD. In univariate Kaplan-Meier analyses standard risk disease, cGVHD, single DLI and day 30 lymphocyte count (LC30) above median, favorably affected overall survival (DLI p=0.002; LC30 p=0.0002, all other variables p&lt;0.0001). Risk status was the strongest factor predicting relapse (28.8 ± 8% and 58.4 ± 7% in SR and HR patients respectively p&lt;0.0001). Fludarabine, degree of T-cell depletion, age, cyclosporine schedule and CD34 dose were not significant. In a Cox regression analysis, only cGVHD (RR, 4.268; p=0.001; 95% CI=1.77–10.25) and standard risk (RR, 0.146; p&lt;0.001; 95%CI=0.06–0.35) remained as independent predictive factors for outcome (Figure A). On landmark analysis after day +120, cGVHD was associated with better OS (p&lt;0.0001) and DFS (p=0.0006) (Figure B), and relapse (21.7± 6% and 51.5 ± 11% in patients with and without cGVHD p= 0.002). Aggressive T-cell depletion, combined with relatively high doses of CD34+ cells had proven to be a key strategy to minimize TRM and severe aGVHD. Similar to unmanipulated PBSCT this approach appears to provide a protective effect of chronic GVHD, but with low late mortality. Figure Figure

Fludarabine-Busulfan Conditioning and In Vivo T-Cell Depletion with Reduced Dose of ATG Followed by Allografting Induces Durable Responses in Patients with Advanced Multiple Myeloma with No Grade III-IV aGvHD.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3029-3029
Author(s):  
Nizar J. Bahlis ◽  
Douglas A. Stewart ◽  
Mary Lynn Savoie ◽  
Christopher Brown ◽  
Andrew Daly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Depletion ◽  
Cell Transplant ◽  
T Cell Depletion ◽  
Grade Iii

Abstract Background: We have investigated a conditioning regimen with Fludarabine and intravenous Busulfan with reduced ATG dose in patients with advanced and poor prognosis myeloma exploring the possibility that a low dose ATG may be sufficient enough to prevent severe GvHD without completely suppressing the graft vs myeloma effect. Methods: 15 patients received a conditioning regimen consisting of fludarabine 50mg/m2 on days -6 to -2 and IV BU (Busulfex, ESP Pharma) at a “myeloablative” dose of 3.2 mg/kg daily days -5 to -2 inclusive. All pts received Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pre-transplant finishing D0, cyclosporine A and methotrexate with folinic acid. Results: The median age was 49 years (range 40–61). 14 (93.3%) patients had stage III (DS) disease with a median β2-microglobulin 3.12 mg/dl (1.82–5.75) and 7/11 (63.6%) in whom FISH studies were available had deletion 13, 5/15 (33.3%) patients had relapsed or progressed within 2 years of prior autologous stem cell transplant and 4 (26.6%) had progressed while on thalidomide /Dex salvage treatment. The disease status prior to allogeneic transplant was partial response (PR) in 6/15 (40%) and progressive disease (PD) in 9/15 (60%). 2/15 had plasma cell leukemia. The median number of bone marrow plasma cells prior to allo-transplant was 16% (range 3%-85%). Donors were matched siblings (MRD) for 13 (86.7%) and alternate donors in 2 (13.3%, unrelated with 2 C antigen mismatch). Cell source was blood in 14/15 (93.3%). Acute GVHD grade II-IV occurred in only 1 patient (6.6%) with no grade III-IV acute GVHD. Chronic GVHD occurred in 9/15 (60%). The TRM was 6.6%. Among 14/15 patients evaluable for response, the overall response rate (CR+PR) was 53.3% (2 CR, 6 PR, 1 MR and 5 PD); 37.5% (1CR, 2PR, 1MR and 4PD) for pts with PD at the time of the transplant and 71.4% (4PR, 1MR and 1PD) for pts with del13. After a median follow-up of 40.9 months (range 36–65.2), the estimated OS and PFS at 4 years for all patients is 38.9% (CI 95%: 13.1–64.7%) and 20.0% (CI 95%: 0–40.3%) respectively. For patients with del13 the estimated OS and PFS at 4 years is 38.1% (CI 95%: 0–77.9%) and 0% respectively. Conclusion: In vivo T-cell depletion with ATG results in a low rate of severe aGvHD with low treatment-related mortality and a substantial number of long-term survivors among patients with advanced multiple myeloma. The detection of deletion 13 by FISH however remains a predictor of short progression free survival. Figure Figure

scholarly journals T Cell Depleted Allogeneic Stem Cell Transplants for Hematological Malignancies: A 20 Year Experience Shows No Relationship Between Choice of Transplanted T Cell Dose or Delayed T Cell Add-Back on Major Outcomes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2013-2013
Author(s):  
Prathima Anandi ◽  
Xin Tian ◽  
Puja D. Chokshi ◽  
Noelle Watters ◽  
Sawa Ito ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Cell Transplant ◽  
T Cell Depletion ◽  
Cell Dose ◽  
Increased Risk

Abstract Introduction: T cell depletion of the stem cell allotransplant (SCT) has the advantage of reducing incidence and severity of GVHD but can be complicated by relapse and infection. An optimum residual T cell dose in T depleted SCT is not known. To optimize T cell depletion we delivered a series of fixed T cell transplant doses with scheduled T cell add back post-SCT in a series of protocols to determine the T cell doses that secured immune reconstitution, and minimized relapse and infection. Here we retrospectively examined large series of patients (pts) transplanted in a single institution where T cell dose at SCT and add back were quantitated. Unique to these protocols was the precise measurement of CD3 dose/kg at transplant for every patient which enabled us to relate transplant T cell doses to outcome. Patients and methods: 205 pts (106 males, 99 females) underwent HLA identical sibling allogeneic T cell depleted SCT between 1994 and 2014. Diagnosis at SCT included AML (48%), MDS (17%), ALL (27%), CLL (5%), MM (3%). Disease risk at SCT was classified as high (57%) or standard (43%). The median age at SCT was 37 (range: 10-75) yrs. TBI based myeloablative conditioning was used. The graft source was marrow in 20 pts and peripheral blood in 195 pts. GVHD prophylaxis was low dose cyclosporine. Different T cell depleted methods were used consecutively: elutriation, Isolex ®, Cellpro ® CD34, and Miltenyl © CD34 selection. A defined T cell dose was allocated at SCT by protocol ranging from 2 - 50 × 104 CD3+ cells/kg. Various schedules were used to add back T lymphocytes between day 30 to 90 with doses ranging 5 - 60 ×106 CD3+ cells/kg by protocol and no T cell add-back was given in 28 pts in recent protocols. Overall survival (OS) was estimated by the Kaplan-Meier method, and cumulative incidence of relapse and nonrelapse mortality (NRM) was estimated by Gray's method to account for competing risks. Cox proportional hazard regression models were used to assess the association of factors at baseline, day 100 and GVHD with the post-SCT outcomes. Results: At a median follow-up of 8.6 yrs (range: 0.7- 19.8) for surviving pts, 112 pts died (52 from NRM) and 68 pts relapsed. OS was 47%, 43% and 41%, NRM was 24%, 27% and 27%, relapse was 32%, 34% and 38% at 5 yr, 10 yr and 15 yr post SCT, respectively. Grade II-IV and III-IV acute GVHD were 41% and 13%, and chronic GVHD was 42% (25% limited, 17% extensive). In the multivariate models of baseline risk factors that adjusted for age at SCT and disease risk, T-cell doses at SCT did not affect OS, NRM or relapse. A higher dose of CD34+ cells at SCT was significantly associated with better OS and lower NRM. Disease risk was an independent predictor, with high-risk pts having more relapse and worse OS, compared to pts with standard risk. A landmark analysis of 156 pts surviving and relapse-free beyond day 100 was carried out to examine the effects of add back T cell schedules by day 100 and aGVHD. The total T-cell dose at add back by day 100 and different add-back T-cell schedules from day 30-90 had no impact on any outcome, controlling for T-cell dose at SCT. In the models controlling for age, risk, CD34+ and T-cell dose at SCT, pts with grade III-IV aGVHD by day 100 had an increased risk for overall mortality and NRM beyond day 100 (HR= 3 and 3.6, both P<0.001), but did not affect relapse. An analysis of pts surviving and relapse-free beyond 1 yr showed pts with extensive cGVHD had higher NRM rate (39%) and lower relapse rate (0%) after 1 yr post-HSCT compared to pts with no cGVHD ( NRM, 9%, P = 0.020; relapse 24%, P=0.026). Conclusion: These findings indicate that for myeloablative matched sibling SCT there is no ideal prescription of T cell dose at transplant within a range of 104 - 105 or for scheduled add back of lymphocytes within a range of T depletion 5 - 60 × 106. Instead, factors other than T cell dose either at transplant or when add-back was delayed determined GVHD incidence, relapse, and survival. These findings set a limit on the efficacy of any T cell depletion procedure to optimize transplant outcome. Disclosures No relevant conflicts of interest to declare.

Improved Long Term Survival with Minimal GVHD after Myeloablative Unrelated Donor Stem Cell Transplantation Using In Vitro and In Vivo T Cell Depletion with CAMPATH-1H.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2761-2761
Author(s):  
Peter A. von dem Borne ◽  
Floor Beaumont ◽  
Ingrid Starrenburg ◽  
Machteld A. Oudshoorn ◽  
Geoff Hale ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Related Mortality

Abstract In allogeneic stem cell transplantation (SCT) T-cell depletion reduces transplant related mortality by diminishing GVHD. We have investigated a myeloablative regimen for matched unrelated donor SCT using both in vivo and in vitro CAMPATH-1H for effective T-cell depletion, utilising DLI at a later time point for graft versus tumor effect if necessary. Thirty patients (median age 33 years, range 18–48) were transplanted from January 1997 to June 2002. Diagnoses were: CML CP (n=9), CML AP (n=2), AML/MDS (n=9), ALL (n=8), NHL (n=1) and Fanconi anemia (n=1). Six patients had one HLA mismatch, the others were identical for HLA A, B, C, DR and DQ. Conditioning consisted of CAMPATH-1H 5mg/d on days −8 to −4, TBI 6 Gy on days −8 and −7 and cyclofosfamide 60 mg/kg on days −6 and −5. T-cell depletion was performed by in vitro incubation of the graft with 20 mg CAMPATH-1H for 30 minutes (Campath “in the bag”). Post-transplant GVHD prophylaxis consisted of cyclosporine A and methotrexate. The stem cell source was bone marrow in 19 patients (63%) and peripheral blood in 11 patients. One graft failure was observed, all other patients had sustained engraftment of donor cells. Acute GVHD was observed in 12 patients (40%), maximally grade I-II skin. No severe acute GVHD (grade III-IV) was experienced. Limited chronic GVHD developed in 2 patients, resolving after treatment. Only in one patient extensive chronic GVHD developed, which did not resolve. CMV reactivation occurred in 23% of patients, one patient developed CMV disease. No EBV disease was observed. Ten patients received donor lymphocyte infusion (DLI) at a median of 17.4 months after SCT (8 patients with relapsed CML, one patient with relapsed ALL, one patient with autoimmune hemolytic anemia). After DLI acute GVHD grade I-II developed in 4 patients, and GVHD grade III-IV in 3. Chronic GVHD developed in 5 patients, of which 2 extensive, resolving in all except one patient. With a median follow up of 37 (range 21–84) months 17 patients are alive (57%). One of the CML patients shows persistence of molecular disease not responding to increasing doses of DLI. All other patients are in CR with the CML patients in molecular remission. Five patients (17%) died because of relapsed disease (2 AML/MDS and 3 ALL). Treatment related mortality was 26% (1 rejection, 2 GVHD, 1 myocardial infarction, 4 infections). In conclusion, matched unrelated donor SCT following myeloablative conditioning using T-cell depletion with CAMPATH-1H in vivo as well as in vitro results in good engraftment, minimal grade I-II GVHD and an overall survival of 57%. Relapse rate was not increased with this strategy. This regimen appears to be successful for young adults with high-risk malignancies.

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