Alemtuzumab (Campath 1-H) Exposure Correlates with Risk of Chronic Graft vs Host Disease and CMV Viremia after Allogeneic Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1818-1818
Author(s):  
Justin P. Kline ◽  
Rajiv Swamy ◽  
Dezheng Huo ◽  
Laura Michaelis ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
At Risk ◽  
Half Life ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Absolute Lymphocyte Count ◽  
Enzyme Linked Immunosorbent Assay ◽  
Unrelated Donor ◽  
Increased Risk ◽  
Cmv Reactivation

Abstract Conditioning regimens using in vivo alemtuzumab (Campath-1H, humanized anti-CD52) are characterized by low rates of acute and chronic GVHD, but may also result in delayed immune reconstitution. Optimization of such regimens will depend on an understanding of the relation between alemtuzumab exposure, immune reconstitution and GVHD. We have conducted a prospective study of fludarabine 30 mg/m2/d x 5 days, melphalan 140 mg/m2 x 1 day and alemtuzumab 20 mg/d x 5 days as conditioning for related and unrelated allografts. Using an enzyme-linked immunosorbent assay (ELISA), we determined serum free and total Campath levels in 46 patients with hematologic malignancies (45) or sickle cell disease (1) on day 0, day 7, day 14, day 28, day 50, day 75, day 100, day 150 and at one year after transplant (HSCT). 26 (57%) had a matched sibling donor, 16 (35%) a matched unrelated donor (MUD) and 4 (9%) a mismatched related or unrelated donor. 44 pts engrafted and are included in the analysis. Median follow up for survivors was 2.8 years. Grade II–IV aGVHD occurred in 8 pts after a median of 42 days (range 22 to 60). Eight pts developed cGVHD after a median of 107 days (range 89–140). 15/41 (37%) at risk pts developed CMV reactivation. The half-life of free alemtuzumab (fA) was 26 days after HSCT with wide interpatient variation in fA pharmacokinetics (e.g. Coefficient of variation was 138% on day 0). On day 0, 1 patient had an undetectable level of fA. By day 28, 50, and 100, there were 6 (14.6%), 12 (35.3%), and 13 (52%) pts with undetectable fA, respectively. Figure 1 shows the fitted means and 95% confidence intervals of fA over time. Using log-rank and Cox proportional hazard models, there was no association between fA on day 0, day 28, or the last available fA, and development of acute GVHD. However, pts with higher average free and total Campath levels in the first month had a lower risk of developing cGVHD (p=0.02). The median fA concentration in the first month for pts with cGVHD was 0.32 (inter-quarter range IQR: 0.22–0.41), as compared with 0.97 (IQR: 0.23–3.31) in those without cGVHD. No significant association between absolute lymphocyte count and fA concentration was found after adjusting for time (p=0.28). Finally, among pts at risk, a higher fA concentration on day 0 (p=0.002), and in the first month (p=0.003) was significantly associated with CMV viremia. In summary, the estimated half-life of serum fA is 26 days after HSCT, but with considerable interpatient variability. Higher concentrations of fA were associated with a decreased incidence of cGVHD, but an increased risk of CMV reactivation. In contrast to a previous preliminary analysis, no association existed between fA and lymphocyte reconstitution. Variation in alemtuzumab pharmacokinetics may predict important clinical outcomes, such as cGVHD and CMV reactivation. Future studies are warranted to determine an optimal alemtuzumab exposure that hastens immune reconstitution while minimizing chronic GVHD. Fig 1. Fitted Mean Free Campath and 95% CI Fig 1. Fitted Mean Free Campath and 95% CI

Campath-IH Combined with Fludarabine/Cyclophophamide/Rituximab (FCR) as Conditioning for Unrelated Non-Myeloablative Hematopoietic Transplantation (NMT) for Non-Hodgkin’s Lymphoma (NHL): Low Mortality Rate and Lower Than Expected Incidence of Cytomegalovirus (CMV) Reactivation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2902-2902
Author(s):  
Issa F. Khouri ◽  
Jeffrey J. Tarrand ◽  
Grace-Julia Okoroji ◽  
Rima M. Saliba ◽  
Chitra M. Hosing ◽  
...  
Keyword(s):  
Disease Progression ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Progression Free Survival ◽  
Unrelated Donor ◽  
Positive Serology ◽  
Hematopoietic Transplantation ◽  
Cmv Reactivation

Abstract Graft-versus-host disease (GVHD) remains a significant cause for morbidity following unrelated hematopoietic transplantation. We investigated the addition of Campath-IH in vivo, at a total dose of 45 mg, to the FCR conditioning regimen for unrelated NMT for relapsed chemosensitive NHL. 25 consecutive patients (pts) with various lymphoid histologies {Follicular = 9, Mantle cell = 7, Large cell =9}were treated. Median age was 52 yrs (range, 31–64). Median # of prior chemoregimens received was 3, and 5 pts (20%) had failed a prior autologous transplant. Ten pts (40%) were in complete remission, and 15 (60%) had evidence of active disease at study entry. Pts received rituximab at 375 mg/m2 on day −8, −1, +6 and +13. Campath-IH 15 mg/iv was given daily on days −4,−3,−2. Chemotherapy was provided on the same days as the Campath-IH and consisted of fludarabine 30 mg/m2/day x 3, and cyclophosphamide 1000 mg/m2 /day x 3. Transplantation was given on day 0. Bone marrow was the source of graft in 20 pts (80%), and 5(20%) received peripheral blood. Tacrolimus (maintained at a low trough level of 5) and methotrexate were used as additional GVHD prophylaxis. Median time to recovery of an ANC>500 was 11 days (range, 9–21). Nine pts (36%) did not require any platelet transfusions. All pts engrafted donor cells (median 81%, at 30 days); 19 pts remained mixed chimera at the time of their last follow-up. Five pts required donor lymphocyte infusion (DLI) for disease progression: 3 achieved complete, one partial and one had no response. With a median follow-up time of 16 mos (range, 3–45 mos), overall survival was 90% (95%CI, 66–99), and the current progression-free survival rate was 68% at 18 mos. Acute GVHD occurred in one pt (grade 1) pre-DLI, and in 3 pts (one grade 1, one grade 2, and one grade 3) post DLI. Chronic extensive GVHD occurred in 3 pts pre-, and 2 additional pts post DLI. Two pts died: one of chronic GVHD, and one of disease progression. Seventeen of the 25 transplants had either the recipient or the donor with CMV-positive serology. CMV prevention consisted of a once daily dose of foscarnet, and twice-weekly screening using the CMV Direct Antibody Fluorescent Stain Antigenemia test. With this strategy, only 9 pts (36%) had evidence of CMV reactivation (defined as any detection of CMV cells). No pt developed or died from CMV disease. These data suggest that unrelated NMT after Campath-FCR conditioning is associated with a low incidence of GVHD and treatment-related mortality. Foscarnet prevention with bi-weekly CMV screening is associated with a lower than expected risk for CMV reactivation. The regimen is a promising approach for unrelated donor transplantation for patients with advanced lymphoma.

Virus Reactivation Profile as Assessed by PCR and Serology Pattern Following First-Line Alemtuzumab (Anti-CD52 Monoclonal Antibody, Campath®) Therapy in Patients with B-CLL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 968-968
Author(s):  
C. Karlsson ◽  
H. Dahl ◽  
A. Linde ◽  
J. Lundin ◽  
M. Björkholm ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Parvovirus B19 ◽  
Viral Reactivation ◽  
Nuclear Antigen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Repeated Treatment ◽  
Virus Reactivation ◽  
First Line ◽  
Increased Risk ◽  
Cmv Reactivation

Abstract Alemtuzumab (Campath®) has shown promising results in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) as first-line therapy and in fludarabine-refractory disease (Lundin, Blood 2002; Keating, Blood 2002). Alemtuzumab induces depletion of all lymphoid subsets, which may persist for a prolonged period of time (Lundin, Leukemia 2004). As a result, an increased risk of infection has been associated with alemtuzumab therapy, in particular cytomegalovirus (CMV) reactivation causing symptomatic disease in 10%–30% of patients. It is of importance, therefore, to study the incidence of clinical and subclinical reactivation of not only CMV but also other pathogenic viruses, as well as serology patterns, in order to better understand the consequences of the induced immunosuppression and to further evaluate the safety of alemtuzumab therapy in B-CLL patients. In this study, serum samples were analyzed from 18 patients with B-CLL who achieved long-lasting unmaintained remissions following first-line alemtuzumab SC therapy (Lundin, Blood 2002). Quantitative real time PCR was used to detect and measure the presence of CMV, Ebstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), and parvovirus B19. Analyses were conducted at the following timepoints: baseline; Months 1, 2, and 3 of alemtuzumab therapy; end of treatment; 6 and 12 months post-alemtuzumab therapy. The presence of serum immunoglobulin G (IgG) antibodies against CMV, varicella-zoster (VZV), Morbillivirus, Epstein-Barr Nuclear Antigen-1 (EBNA1) protein of EBV, and Streptococcus pneumoniae were detected by Enzyme-Linked Immunosorbent Assay (ELISA), and EBV viral capsid antigen (VCA) IgG by immunofluorescence (IF). All 18 patients with B-CLL responded (PR or CR) to alemtuzumab therapy. Median time to treatment failure was 34 months (range, 9–71+). There were 9 episodes of viral reactivation (5 CMV after 1–2 months of therapy; 3 EBV at baseline; 1 HHV-6 after 1 month of therapy) measured by PCR in 8 patients (44%) during the study period. The median number of genome equivalents/mL was 2,600 (range, 1,300–81,400). A retrospective analysis of the case records revealed that 3/5 episodes of CMV reactivation correlated to discrete clinical symptoms (transient, grade I fever or temporary cough), which were not diagnosed as viremia during the clinical part of the study. All 9 episodes of viral reactivation resolved spontaneously, except for 1 patient (in stable unmaintained PR) who had a late recurrence of symptomatic EBV infection 20 months after completion of alemtuzumab therapy. The viral load and symptoms responded to rituximab (anti-CD20 monoclonal antibody, Rituxan®) therapy, but repeated treatment episodes have been required. Most patients had stable IgG reactivities during and after alemtuzumab therapy; however, 6 patients (35%) had a significant decrease in antibody titers: 4 against Morbillivirus and 2 against EBV. These results suggest that virus reactivation is not uncommon in patients receiving alemtuzumab therapy for B-CLL. Notably, most reactivations occurred early during therapy, were asymptomatic or caused discrete symptoms, and usually resolved spontaneously without specific therapy. Additional studies on virus reactivation and long-term studies of virus serology to evaluate the need for vaccination are warranted also in patients with fludarabine-refractory B-CLL receiving alemtuzumab.

Multiple Transplant-Related Risk Factors for Hemolysis Including Major Kidd-Group Incompatibility Did Not Influence the Favourable Course of Unrelated Donor Bone Marrow Transplantation for Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5444-5444
Author(s):  
Miroslaw Markiewicz ◽  
Iwona Wylezol ◽  
Sebastian Giebel ◽  
Malgorzata Krawczyk-Kulis ◽  
Jerzy Wojnar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Effective Treatment Option ◽  
Single Donor ◽  
Related Risk ◽  
Severe Pancytopenia ◽  
Nasal Septum Perforation ◽  
Cmv Reactivation

Abstract The significance of additional transplant-related risk factors for hemolysis, including potentially severe hemolysis due to Kidd group incompatibility, is unknown in BMT from matched unrelated donors (MUD). We report MUD BMT for 35y old male PNH patient (pt) diagnosed 1,5y before, with CD59 defect on 95% of erythrocytes (Er), with refractory hemolysis (LDH 1886 U/l, haptoglobin 0.08 g/l) and IgG autoantibodies on Er, previously treated with steroids and multiple transfusions with increasing frequency. BMT-related risk factors for hemolysis were: major Kidd incompatibility (Jk(b)+ donor and detectable anti-Jk(b) alloantibodies in titer 2 in pt), minor AB0 incompatibility (pt B, donor 0 with anti-B titer 1:16) and different Rh (pt−, donor+). Other risk factors included CMV seronegativity of the donor and seropositivity of the pt, arterial hypertension, steroid-related diabetes mellitus and probable former thrombotic episode leading to nasal septum perforation. MUD was ten alleles HLA-matched 38y old male. Myeloablative conditioning consisted of Treosulfan, Fludarabine and Thymoglobulin. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin-A and methotrexate. Gancyclovir and IgG were used for CMV-reactivation prophylaxis. Transplanted bone marrow was depleted of Er on Fenwall CS3000 plus and contained 0.5x10(8) NC/kg, 2.1x10(6) CD34+ cells/kg and 12.5x10(6) CD3+ cells/kg. No serious complications were observed during the treatment and post-transplant aplasia. Filtered washed Er 0Rh-Jk(b)- were transfused 7x and single-donor platelets 7x. Following 11 days of absolute agranulocytosis full reconstitution of haematopoiesis was achieved with granulocyte count of 1.0x10(9)/l and platelets 50x10(9)/l on day +22, Hb 10 g/dl on day +26. Acute GVHD grade II was transiently present since day +21 and responded well to low-dose methylprednisolone. No chronic GVHD was observed. CMV reactivation with transient severe pancytopenia developed after day +70 and was overcome with ganciclovir, foscarnet and immunoglobulins. Hemolysis gradually decreased (LDH less than 400 U/L since day +5, normal haptoglobin >0.7 g/l since day +38). Anti-Jk(b) alloantibodies titer reached 0 on day +31 and since then they were detectable only with use of a micro-method. Full 100% donor chimerism was achieved on day +28 and was re-confirmed on days +71 and +99. Recipient-type population of erythrocytes gradually decreased (24%, 7% and 1% on days +30, +70 and +98, respectively). Complete eradication of PNH clone was confirmed by absence of complement inhibitor CD55 (DAF) and CD59 (MIRL) defects on 100% of erythrocytes and granulocytes in flow-cytometric evaluation performed on day +160. The patient stays at home without any signs of GVHD, hemolysis nor PNH over 9 months following BMT. We conclude that MUD BMT can be offered as an effective treatment option despite multiple transplant-related risk factors for hemolysis including Kidd group incompatibility.

Alemtuzumab Reduces Chronic Graft Versus Host Disease (cGVHD) and Treatment Related Mortality (TRM) after Reduced Intensity Conditioning for AML and MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1076-1076 ◽  
Author(s):  
Koen van Besien ◽  
Marcos de Lima ◽  
Andrew Artz ◽  
Betul Oran ◽  
Wendy Stock ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Cancer Center ◽  
P Value ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Md Anderson

Abstract In vivo T-cell depletion with alemtuzumab has been used to reduce acute and chronic GVHD. In order to evaluate its overall effect on transplant outcomes in AML and MDS we compared 90 pts who received fludarabine/melphalan/alemtuzumab (FMA) conditioning and post-transplant tacrolimus at the University of Chicago, with 112 who received fludarabine/melphalan (FM) and post-transplant tacrolimus/methotrexate at MD Anderson Cancer Center. Pt and transplant characteristics were well balanced except for a higher proportion of MDS in the FM group. Median age, proportion unrelated donor tx and proportion high/intermediate and low risk by ASBMT criteria were balanced between the groups. With median follow up of 28 months in both groups, one year progression free survival and overall survival are identical. TRM is significantly higher after FM, but relapse is higher in FMA. 19/103 d 28 survivors after FM vs 7/84 after FMA developed gr III–IV acute GVHD (p=0.04). 46/77 d100 survivors after FM developed ext cGVHD vs 7/63 after FMA (p=0.0000). 43 patients remain alive after FM and 27 have ext cGVHD. 41 remain alive after FMA and 1 has ext cGVHD. Alemtuzumab results in a considerable reduction in acute and particularly chronic GVHD. TRM is reduced compared with standard GVHD prophylaxis. Low incidence of chronic GVHD and reduced TRM may be the major benefit of this strategy. Relapse rates are increased, because of reduced GVL effects or because of improved early survival of high risk patients. Other approaches are necessary for improving long term outcomes. Patient Characteristics and Outcome FMA FM P-value N 90 102 Age (range) 54 (22–74) 51 (17–77) 0.6 AML/MDS 13/77 29/83 0.04 MUD/related 42/48 59/63 0.5 High./Intermediate/LowRisk 48/13/28 76/10/26 0.12 Median Follow up mths (range) 28 (3–89) 28 (1–66) 0.07 TRM@ 100 days 13% + 7% 24% + 8% 0.04 TRM@ 1 year 30% + 12% 42% + 10% 0.04 Relapse @ 1 year 40% + 12% 26% + 10% 0.01 PFS @ 2 years 33% + 11% 37% + 9% 0.9 OS @ 2 year 42% + 11% 44% + 9% 0.5 AGVD gr III–IV 7/84 19/103 0.04 Ext cGVHD 7/63 46/77 0.0000 Ext cGVHD in survivors 1/41 27/43 0.0000

Delayed Cytomegalovirus (cmv) Infection Following Hematopoietic Cell Transplantation (HCT): City of Hope (COH) Experience.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1155-1155
Author(s):  
Alexandra Schaible ◽  
Allison Mays ◽  
Can-Lan Sun ◽  
Liton Francisco ◽  
Lennie Wong ◽  
...  
Keyword(s):  
Immunosuppressive Therapy ◽  
Chronic Gvhd ◽  
First Year ◽  
Unrelated Donor ◽  
Cmv Infection ◽  
Allogeneic Hct ◽  
Increased Risk ◽  
Related Donor ◽  
Autologous Hct ◽  
One Year

Abstract Patients undergoing HCT are at an increased risk of developing primary and/or reactivated CMV infection, although the magnitude of risk of CMV disease has decreased with the widespread use of preemptive ganciclovir. Most episodes of reactivation occur within the first year post-HCT and are associated with risk factors such as CMV serostatus of donor and recipient, development of acute graft vs. host disease (GVHD): and the immunosuppressive therapy used for its management. Because of prolonged periods of immunosuppression post-HCT, patients may be at risk for delayed CMV infection one or more years after HCT. However, the magnitude of risk of delayed CMV infection and characteristics of those at increased risk has not been described. Given the high morbidity and mortality associated with post-HCT CMV infection, identifying patients at high risk of delayed CMV could be useful for effective management. This report includes 2700 consecutive patients who survived more than one year after undergoing HCT at COH between 1976 and 2003; these included 1404 autologous HCT recipients and 1296 allogeneic HCT recipients (1043 related donor; 253 unrelated donor recipients). Median age at HCT was 38 years (range, 0.6 to 79 years) and 59% of the cohort was males. Median follow-up time from HCT until delayed CMV infection/disease, death, or end of study period (12/31/2006), whichever occurred first, was 4.3 years (range:1–26.6 years). Medical records from COH and/or outside facilities were the main source of data for CMV occurrences. In total, 33 patients (1%) developed delayed CMV infection after surviving at least one year post-HCT (1 autologous and 32 allogeneic [20 related donor and 12 unrelated donor HCT]) developed a total of 40 episodes of delayed CMV that included pneumonia (n=16), gastrointestinal disease (n=8), retinitis (n=2), hepatitis (n=1), concurrent pneumonia and hepatitis (n=1), and asymptomatic reactivation (n=12). The overall cumulative incidence of delayed CMV infection was 1.3% (95% Confidence Interval [CI], 0.9–1.8%) at 5 years from HCT. For autologous HCT recipients, the incidence was 0.07% at 1 year based on 1 event. Among allogeneic HCT recipients, the cumulative incidence at 5 years post-HCT was 2.1% [95%CI, 1.2–3.0%] for related donor HCT recipients; and 5.0% [95%CI, 2.2–7.7%] for unrelated donor HCT recipients. Among allogeneic HCT recipients, the risk factors for the development of delayed CMV infection included unrelated donor HCT (hazard ratio [HR] = 2.5, 95% CI, 1.1–5.7) and CMV seropositive status of the recipient (HR=7.7, 95% CI 1.0–57.0) (Figure). Interestingly, donor CMV status was not associated with increased risk of delayed CMV. All 32 allogeneic HCT recipients experienced chronic GVHD, with prolonged exposures to corticosteroids (median=494 days), and cyclosporine (median=380 days). Thirty patients with delayed CMV infection (94% of the allogeneic HCT recipients with delayed CMV) were receiving immunosuppressive therapy for management of chronic GVHD at onset of delayed CMV. A total of eight patients with delayed CMV did not have a history of CMV infection in the first year, and were characterized by the following clinical and demographic features: 6 (75%) were male; median age at HCT was 35 years; one was an autologous HCT recipient, who relapsed 10 months post-HCT for non-Hodgkin lymphoma, received further chemotherapy and radiation, including Rituximab and then developed late CMV, just over one year post-HCT. The seven allogeneic HCT recipients had chronic GVHD, and were CMV serostatus positive prior to HCT, with 4 also having CMV seropositive donors. Of the 33 patients with delayed CMV in this study, 26 expired; median survival after the development of delayed CMV was 46 days. This study describes the magnitude of risk of delayed CMV infection in autologous and allogeneic HCT recipients and identifies at risk patients as those who are seropositive for CMV, undergoing unrelated HCT, and those with prolonged exposures to immunosuppressive therapy for cGVHD (Figure), suggesting the need for a close surveillance of these patients at high risk. Figure Figure

Allogeneic Stem Cell Transplantation (allo-SCT) for Secondary Acute Myeloid Leukemia (AML) Following Breast Carcinoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3305-3305
Author(s):  
Sameh Ayari ◽  
Mohamad Mohty ◽  
Karin Bilger ◽  
Gaelle Guillerm ◽  
Denis Guyotat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Breast Carcinoma ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Increased Risk ◽  
Acute Myeloid

Abstract Abstract 3305 Poster Board III-193 Patients with breast carcinoma who received Radio and/or chemotherapy, have an increased risk for developing therapy-related myelodysplastic syndromes/acute myeloid leukemia (1-5%). Such secondary AMLs have often poor prognosis when treated with conventional chemotherapy. This retrospective series assessed the outcome of 29 female patients who were reported to the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire Registry, and who were treated with allo-SCT for secondary MDS/AML developing after initial therapy for breast cancer. The median age of patients at time of breast cancer treatment was 51 (range, 31-62) years. The median age at time of allo-SCT was 53 (range 31-63) years. Diagnosis included 21 AML and 8 MDS. Cytogenetics: four patients had CBF abnormalities, 10 had 11q23 abnormalities, 5 had an intermediate caryotype and 3 had unfavourable one. At time of allo-SCT, 21 patients were in complete remission (CR), while 8 had a refractory/relapsed disease. PBSCs were used as stem cell source in 18 patients, while 9 patients received classical bone marrow and one patient received an unrelated umbilical cord blood. Patients received a median of 5.2 ×10e6/Kg CD34+ cells. A matched related donor was used in 23 cases (82%) and an unrelated donor in 5 cases (18%). Conditioning regimen was myeloablative (Cy-TBI or Bu-Cy) in 7 cases (24%) and reduced-intensity in 22 cases (76%). Twenty four patients engrafted with a median time of 18 (range, 9-32) days for ANC>500/μL. Seven (24%) patients experienced grade 2-4 acute GVHD. Also, 7 patients (24%) experienced chronic GVHD (5 extensive and 2 limited). With a median follow-up of 24 (range, 3-129) months, 16 patients (55%) were still alive. Disease progression accounted for 6 deaths while transplant related causes (infection n=4, GVHD n=1, MOF n=1, cardiac failure n=1) occurred in 7 cases. The Kaplan-Meier estimates of overall and disease-free survival at 2 years were at 54 and 38% respectively. These results highlight the poor outcome of secondary leukemia occurring after therapy for breast cancer, even with the use of allo-SCT. Innovative maintenance approaches such as early use of hypomethylating or immunomodulatory agents after allo-SCT aiming to decrease the relapse are warranted. Disclosures No relevant conflicts of interest to declare.

Adoptive Transfer of CMV-Specific Donor T Cells Following Allogeneic Transplantation Leads to Rapid and Safe Systemic Reconstitution.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 44-44
Author(s):  
Karl S Peggs ◽  
Kirsty Thomson ◽  
Edward Samuel ◽  
Gemma Dyer ◽  
Julie Armoogum ◽  
...  
Keyword(s):  
T Cells ◽  
Drug Therapy ◽  
T Cell ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Antiviral Drug ◽  
Donor T Cells ◽  
Post Infusion ◽  
Cmv Reactivation

Abstract Abstract 44 Reactivation of CMV remains a significant problem following allogeneic hematopoietic stem cell transplantation. Antiviral drug therapy is effective but toxic, and resistant strains of CMV are increasingly being reported. Virus-specific T lymphocytes are necessary for the control of viral reactivation. Adoptive transfer of donor derived CMV-specific T cells has been reported previously but most methods to produce such cells have involved several weeks of in vitro culture or have produced a therapeutic product restricted to CD8 T cells. The current method involves a short incubation of donor peripheral blood mononuclear cells with either CMV-pp65 protein (20 hours) or a pool of peptides from pp65 (6 hours) with subsequent isolation of interferon-gamma secreting cells by CliniMACS using IFNψ capture microbeads (Miltenyi Biotec). This technique permits rapid isolation of an enriched IFNψ secreting T cell product, manufactured to clinical grade, which is then cryopreserved in dosed aliquots for subsequent infusion. Here we report the outcome of a single arm phase I/II in which CMV-T cells given pre-emptively at first detection (qPCR) of CMV DNA in peripheral blood, or at day +40-60 as prophylaxis. CMV replication was monitored by weekly PCR and reconstitution of CMV-specific T cells by pentamer labelling and/or IFNψ secretion assay. Conventional antiviral drug therapy was instituted if the viral load rose above institutional threshold. 30 recipients of T cell depleted low intensity transplants from HLA-matched CMV-seropositive related donors were enrolled between 2006 and 2008. Donors underwent a second, short apheresis procedure approximately 15 days after collection of the mobilised HPC-A for the collection of CMV-T cells. 26 clinical-grade products were produced to full cGMP standards; four donors were unsuitable or withdrew. The mean yield of cells following enrichment was 41.7% with a median purity of 43.9% (range 1.4-81.8). Adequate CMV-T cells were isolated from all donors. Both pp65 and peptide stimulated products contained both CD4 and CD8 reactive T cells. Median dose of CMV-specific CD4 T cells was 2840/kg and of CMV-specific CD8 was 630/kg. Eighteen patients received a single dose of 1×10^4 CD3+/kg; 13 were CMV seropositive; 11 were treated pre-emptively and 7 prophylactically. 83% had received T cell deplete regimens. Within 2 weeks of infusion in vivo expansion of CMV-T cells was observed in 17 of 18 patients. One patient required 4 weeks to generate detectable CMV-T cell in his peripheral blood. TCR-BV usage of the CMV-T cells post infusion matched that of the cells which had been infused. The 7 patients who had cells infused prophylactically all showed expansions of CMV-T cells in the absence of detectable viral DNA in peripheral blood. Subsequent low level CMV-reactivation was seen in one of these and was associated with rapid CMV-T cell expansion with clearance of virus without anti-viral drug therapy. One developed subsequent extensive chronic GvHD and required antiviral treatment for multiple reactivation episodes following introduction of steroids. Of the 11 patients treated pre-emptively, 9 received antiviral therapy for the initial reactivation, although in 7 patients this was required for only 7-15 days. (compared to a median of 21 days in historical controls). Three patients had a further CMV reactivation event. One followed prednisolone therapy for acute grade II GvHD. The second was the patient who had shown poor T cell expansion post infusion and had required prolonged anti-viral therapy (33 days) for the initial CMV reactivation. The third patient received no treatment and cleared virus following a further in vivo expansion of CMV-reactive T cells, suggesting the presence of a functional memory population. GVHD incidence and severity was no worse than seen in comparable historical controls. 3 patients suffered grade 2-3 acute GvHD. 3/17 evaluable patients developed extensive chronic GvHD (2 were recipients of T replete grafts). 16/18 patients were alive at the end of the 6 month monitoring period and CMV-reactive T cells were detectable in all 16. CMV-specific donor T cells can be readily produced to cGMP compliance which can be safely infused and lead to early immune reconstitution in at-risk patients. Cells expand in response to subsequent CMV-reactivation and patients appear to require fewer anti-viral treatment episodes which is being tested in an ongoing phase III trial. Disclosures: Lowdell: Cell Medica Ltd: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

A Retrospective Study of Alemtuzumab Level, T Cell Chimerism and Graft Versus Host Disease Using Intermediate Dose Alemtuzumab for Matched Related and Matched Unrelated Reduced Intensity Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3333-3333
Author(s):  
Andrew Charlton ◽  
Laura Spence ◽  
Venetia Bigley ◽  
Natasha Groves ◽  
Geoff Hale ◽  
...  
Keyword(s):  
T Cell ◽  
Linear Regression ◽  
Surface Area ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Full Dose ◽  
Cell Engraftment ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Abstract 3333 Poster Board III-221 Alemtuzumab (CAMPATH 1H) is a well established agent for effecting in vivo T cell depletion and prevention of GVHD in reduced intensity transplants. Many studies indicate that full dose alemtuzumab (100mg in 5 daily doses of 20mg) induces profound immunodeficiency, almost completely ablating GVHD in Fludarabine and Melphalan (FM) matched related donor (MRD) and matched unrelated donor (MUD) transplants. In contrast, FM conditioning alone exposes patients to a high burden of acute and chronic GVHD. Accordingly, many transplant centres have adopted policies of intermediate alemtuzumab dosing of 50mg or less. While the pharmacokinetics, rate of T cell engraftment and incidence of GVHD are well described using full dose alemtuzumab, much less is known about the in vivo action of alemtuzumab at intermediate doses. Methods We report our experience of alemtuzumab at 30mg (day -2) for MRD and 60mg (30mg day -4 and day -2) for MUD transplants, which was adopted as standard GVHD prophylaxis for FM transplantation at our centre in 2006. We avoided giving alemtuzumab on day -1, since there is a steep drop in alemtuzumab level in the first 24 hours after infusion and the timing of stem cell infusion may vary considerably, especially with unrelated donor grafts. From May 2006 to May 2009, 24 patients received MRD and 27 patients received MUD transplants. Post transplant serum samples were available from 19 MRD transplants and 15 MUD transplants at day +1. In addition, day +3 samples were identified from 10 patients previously transplanted with 100mg alemtuzumab, 10 MUD receiving 60mg and 10 MRD transplants receiving 30mg. All patients gave consent for clinical follow up and post transplant serum sampling for research purposes, according to protocols approved by the local research ethics committee of Northumberland and North Tyneside. Alemtuzumab concentration was measured by a validated flow cytometry assay, as previously described. Results The mean (SEM) alemtuzumab concentration (micrograms/ml) on day +1 was 2.9 (0.3) after 30mg and 4.6 (0.6) after 60mg (t test p<0.01). On day +3 the levels were 2.4 (0.2); 4.0 (0.6); 8.4 (1.9) after 30mg, 60mg and historical controls of 100mg, respectively (p<0.05 between each dosing level). There were significant inverse correlations between patient surface area and alemtuzumab concentration by linear regression for both 30mg (r2 0.51 p<0.01) and 60mg dosing (r2 0.18 p<0.05). A trend for lower alemtuzumab with increasing cell dose was also observed, although this may be related indirectly to patient weight. All patients achieved >95% myeloid engraftment by day 100. Median (range) T cell engraftment was variable and significantly higher after MUD transplants: 70% (9-99%) than MRD transplants: 21% (5-85%; Mann Witney p <0.05). T cell chimerism was inversely correlated with alemtuzumab level in MRD transplants by linear regression (r2 0.37; p <0.05) but this trend was not apparent in MUD transplants. The incidence of acute GVHD was also greater after MUD transplantation at 47% (grade I or II) compared with 11% (grade I only) for MRD recipients. There was no significant relationship between GVHD grade and alemtuzumab level in either group. There were 2/24 non-relapse deaths after MRD and 3/27 following MUD transplantation; none were due to GVHD. The incidence of chronic GVHD is currently being evaluated. Conclusion This analysis demonstrates predictable dose and surface-area relationships with alemtuzumab level in patients receiving FM conditioning. It also reveals that significantly less than 100mg alemtuzumab confers reliable GVHD prophylaxis in both MRD and MUD recipients, although at least twice the level of alemtuzumab is required to achieve comparable GVHD control in MUD transplants. Finally, it is notable that T cell chimerism at day 100 is directly related to alemtuzumab level at day +1 in MRD transplants. We conclude that optimisation of immune reconstitution and GVHD control using alemtuzumab in vivo depends upon due consideration of both recipient and donor factors, notably the size of the recipient and the origin of the graft. Disclosures Groves: BioAnaLab: Employment. Hale:BioAnaLab: Employment, Equity Ownership.

Impact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignanciesimpact of In Vivo T-Cell Depletion on Outcome of Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2305-2305 ◽  
Author(s):  
Robert J Soiffer ◽  
Jennifer LeRademacher ◽  
Vincent T Ho ◽  
Fangyu Kan ◽  
Andrew Artz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hazard Ratio ◽  
Cell Depletion ◽  
P Value ◽  
Unrelated Donor ◽  
T Cell Depletion

Abstract Abstract 2305 HCT using RIC regimens has increased steadily over the past decade. In vivo administration of anti-T cell antibodies, such as alemtuzumab and anti-thymocyte globulin (ATG) preparations, is often employed to promote engraftment and limit graft-versus-host disease (GVHD). While these antibodies might reduce the severity and incidence of GVHD, they may also blunt the allo-immune graft-versus-tumor effect of HCT. Transplant outcomes after in vivo T-cell depletion (n=584 ATG; n=213 alemtuzumab) were compared to those after T-cell replete (n=879) RIC transplants for myeloid and lymphoid malignancies. Patients were aged 21–69 yrs and transplanted from 2000–2007. Median follow-up of patients is 3 years. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan, or cyclophosphamide) with fludarabine. 792 patients (47%) received allografts from a HLA-matched sibling, 650 (39%) from an 8/8 and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling HCT, 57% of 8/8 and 64% of 7/8 HLA matched unrelated donor HCT. Results of multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis are shown in Table below. Grade 2–4 acute GVHD was lower with alemtuzumab containing regimens (20%) than ATG containing (41%) or T replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG, and 57% of T replete regimens, respectively. Compared to T-cell replete regimens, relapse risks were higher with ATG and alemtuzumab containing regimens (38%, 49% and 51%, respectively) and non-relapse mortality, higher with ATG containing regimens only. Treatment failure (relapse or death) was higher with both ATG and alemtuzumab containing regimens compared to T replete regimens. Overall mortality was highest with ATG containing regimens. These observations are independent of disease, disease status and donor type including 7/8 HLA-matched HCT. The 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in disease-free and overall survival at 3-years by ATG source or dose. The incidence of EBV-PTLD was higher with alemtuzumab and ATG containing compared to T-cell replete regimens (2% vs. 2% vs. 0.2%). These results suggest in-vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. The routine use of in-vivo T-cell depletion in this setting warrants a cautious approach in the absence of a prospective randomized trial. Alemtuzumab vs. T-cell replete ATG vs. T-cell replete Alemtuzumab vs. ATG Hazard ratio, p-value Hazard ratio, p-value Hazard ratio, p-value Grade 2-4 acute GVHD 0.33, p<0.0001 0.88, p=0.12 0.38, p<0.001 Grade 3-4 acute GVHD 0.42, p<0.0001 0.86, p=0.20 0.48, p=0.001 Chronic GVHD 0.34, p<0.0001 0.69, p<0.0001 0.49, p<0.0001 Non-relapse mortality 1.04, p=0.85 1.34, p=0.01 0.78, p=0.19 Relapse 1.54, p=0.0001 1.53, p<0.0001 1.01, p=0.94 Treatment failure 1.40, p=0.0003 1.46, p<0.0001 0.96, p=0.67 Overall mortality 1.09, p=0.46 1.25, p=0.002 0.87, p=0.22 Disclosures: No relevant conflicts of interest to declare.

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