Sorafenib induces sustained molecular remission in FLT3-ITD positive AML with relapse after second allogeneic stem cell transplantation without exacerbation of acute GVHD: A case report

Endothelial cells are involved in the pathogenesis of acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. These cells express several molecules that can be detected as biologically active soluble forms; serum levels of these molecules may thereby reflect the functional status of endothelial cells. Furthermore, acute GVHD is an inflammatory reaction and endothelial cells function as local regulators of inflammation. We therefore investigated whether differences in preconditioning/pretransplant serum levels of endothelium-expressed molecules (i.e., endocan, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin) were associated with a risk of posttransplant GVHD. Our study should be regarded as a population-based study of consecutive and thereby unselected patients (n=56). Analysis of this pretreatment endothelium biomarker profile by unsupervised hierarchical clustering identified a subset of patients with increased early nonrelapse mortality. Furthermore, low endocan levels were significantly associated with acute GVHD in the liver and gastrointestinal tract, whereas high VCAM-1 levels were associated with acute GVHD in the skin only. Our study suggests that the preconditioning/pretransplant status of endothelial cells (possibly through altered trafficking of immunocompetent cells) is important for the risk and the organ involvement of later acute GVHD.

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Increased levels of immune transcript in patients with acute GVHD after allogeneic stem cell transplantation

Bone Marrow Transplantation ◽

10.1038/sj.bmt.1703807 ◽

2003 ◽

Vol 31 (3) ◽

pp. 183-190 ◽

Cited By ~ 18

Author(s):

M Jaksch ◽

M Uzunel ◽

G Martinez Cangana ◽

M Remberger ◽

J Mattsson

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd

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Isolated Extramedullary Relapse in the Breast of a Patient with Acute Myeloid Leukemia following Allogeneic Stem Cell Transplantation: Case Report and Review of the Literature

International Journal of Hematology ◽

10.1532/ijh97.e0628 ◽

2007 ◽

Vol 85 (2) ◽

pp. 149-153 ◽

Cited By ~ 5

Author(s):

Abderrahman Abdelkefi ◽

Lamia Torjman ◽

Saloua Ladeb ◽

Zeineb Sghaïer ◽

Ramzi Jeddi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Case Report ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Review Of The Literature ◽

Extramedullary Relapse ◽

Acute Myeloid

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Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.

Blood ◽

10.1182/blood.v104.11.299.299 ◽

2004 ◽

Vol 104 (11) ◽

pp. 299-299

Author(s):

Michael Schleuning ◽

Christoph Schmid ◽

Georg Ledderose ◽

Johanna Tischer ◽

Meike Humann ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Chronic Infections ◽

Term Survival

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.

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Effect of Rituximab on the Incidence of GVHD in Lymphoma Patients who Received the BEAM-Conditioning and an Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.4980.4980 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4980-4980

Author(s):

Issa F. Khouri ◽

Rima M. Saliba ◽

Daniel R. Couriel ◽

Grace-Julia Okoroji ◽

Sandra Acholonu ◽

...

Keyword(s):

Stem Cell ◽

B Cells ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Control Group ◽

Study Group

Abstract It has been postulated that B cells functioning as antigen-presenting cells may have an important role in the pathogenesis of GVHD. Depletion of donor cells from B-cells resulted in a low incidence of GVHD in mouse model (Schultz et al. BMT1995:16:289–289). More recently, we observed a lower incidence of chronic (and to a lesser extent acute GVHD) in patients with CLL who received an allogeneic stem cell transplantation after a non-myeloablative conditioning regimen containing rituximab (Exp Hematol32:28–35, 2004). The purpose of this study is to investigate the effect of rituximab on GVHD in the setting of a more intense chemotherapy with BEAM, in patients who received an allogeneic peripheral blood stem cell from HLA-identical siblings. To test this hypothesis, we retrospectively studied 11 consecutive patients with non-Hodgkin’s lymphoma who received BEAM/Rituximab at the M. D. Anderson Cancer Center. We attempted to match these patients by age, donor-recipient gender, and donor-recipient CMV reactivity to a historical control of 44 patients with lymphoma, who received BEAM alone as a conditioning regimen, without the Rituximab. Tacrolimus and methotrexate were used for GVHD prophylaxis in both groups. A total of 10 patients in the study group, could be matched with 19 patients in the control group and were included in the final analysis. The outcome of the 2 groups is shown below: Rituximab-Study Group Control Group -value P No. of patients 10 19 Median age 41 44 0.4 (range) (19–55) (19–60) Patient-Donor sex-matched 9(82%) 18(95%) 0.6 Median # CD34 + cells infused (106/kg) 5.1 4.73 0.1 Patient or Donor CMV+ 9(82%) 18(95%) 0.6 Patient and Donor CMV − 1(10%) 1(5%) Median # prior chemoregimens 3 3 0.9 range (1–8) (1–9) Median follow-up 17 38 range (8–48) (27–77) Acute GVHD 2–4 (n,%) 5(50%) 7(37%) 0.5 Acute GVHD 3–4 (n,%) 3(30%) 5(26%) 0.6 Chronic GVHD (n, % cumulative incidence) 8 (90% + 15) 10 (53% + 12 0.01 Our data suggest that the described protective effect of Rituximab against GVHD in mouse models or in the setting of non-myeloablative allogeneic transplantation, may be overcome by the BEAM. This more intense conditioning regimen may induce more GVHD by enhancing T-cell cytokines release and by causing more gastrointestinal toxicity, thus allowing for a greater antigen presentation.

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Comparison between Anti-Thymocyte Globulin and Alemtuzumab and the Possible Impact of KIR-Ligand Mismatch in Melphalan/Fludarabine Dose-Reduced Conditioning Followed by HLA-Matched and Mismatched Unrelated Stem Cell Transplantation in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.980.980 ◽

2004 ◽

Vol 104 (11) ◽

pp. 980-980

Author(s):

Nicolaus Kroeger ◽

Brownen Shaw ◽

Simona Iacobelli ◽

Tatjana Zabelina ◽

Karl Peggs ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Statistical Significance ◽

High Dose ◽

Grade Ii

Abstract We compared anti-thymocyte globulin (ATG-Fresenius median dose 60 mg/kg: n= 48) with alemtuzumab (Campath-1H 100mg: n=25) in 73 patients with multiple myeloma, who underwent dose-reduced conditioning with melphalan and fludarabine, followed by allogeneic stem cell transplantation from matched (n=63) or mismatched (n=10) unrelated donors. Patients of the ATG group had higher age (median 50 vs 47 years, p=0.05), more prior high-dose chemotherapies (p<0.001), while in the Campath group more bone marrow as stem cell source was used (p<0.001). No primary graft failure occurred in both groups. Patients receiving alemtuzumab had a significant faster engraftment of leukocyte (p=0.03) and of platelets (p=0.02) and a lower incidence of acute GvHD grade II-IV (24 vs 47%, p=0.05). However, after treatment with donor lymphocyte infusion due to persistent disease or mixed hematopoietic chimerism the difference of acute GvHD grade II-IV between alemtuzumab and ATG treated patients did not reach statistical significance (32 vs 47%, p=0.2). No difference in incidence of chronic GvHD was observed (25 vs 33%, p=0.6) More CMV seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs 47%, p=0.001). The cumulative incidence of treatment related mortality at 2 years for ATG and Campath was 29.3% (CI=17–50%) vs 28.5% (CI=15–54%), p=0.7. No significant difference could be observed in the estimated 2 years OS and PFS between ATG and Campath: 53% (CI:38–75) vs 45% (CI:28–73) and 29% (CI:16–54) and 36% (CI: 20–62), respectively. For PFS, in a multivariate analysis relapse to prior high-dose chemotherapy was the strongest negative factor: HR 2.9, p= 0.001. Including only those patients who did not experienced any relapse at time of allogeneic stem cell transplantation the Campath-group had a 2.5 fold higher risk of progression in comparison to the ATG group, but without reaching statistical significance (HR: 2.5, p=0.15). Ten out of 73 patients had KIR-ligand mismatch in GvH direction. While in patients without KIR-ligand mismatch the cumulative incidence of relapse at two years was 50%, none of the KIR-ligand mismatched patients relapsed so far (p=0.02). The immunosuppressive effect from Campath is stronger than ATG resulting in less acute GvHD, but requires more DLI procedures to control diseases and resulted in a trend to a lower PFS in chemosensitive patients. This preliminary data further implicated a major role of KIR-ligand mismatch transplantation in multiple myeloma

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High-Dose Rituximab in the Conditioning Regimen Before Allogeneic Stem Cell Transplantation Reduces the Incidence of Acute Gvhd in B-Cell Lymphomas

Blood ◽

10.1182/blood.v118.21.4546.4546 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4546-4546

Author(s):

Paolo Corradini ◽

Barbara Sarina ◽

Cristiana Carniti ◽

Francesca Patriarca ◽

Angelo Michele Carella ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

B Cell ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Chronic Gvhd ◽

High Dose ◽

Unrelated Donors

Abstract Abstract 4546 Background: Reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed lymphomas. The present GITMO study is a prospective multicenter phase II trial for patients affected by relapsed CD20 positive lymphomas. Compared with the previous thiotepa/fludarabine/cyclophosphamide GITMO protocol (Leukemia 2007), the thiotepa dose is increased, and high-dose Rituximab is included in the regimen to improve the outcome and possibly modulate the incidence of acute GVHD. Aims: Primary end-point was 1-year progression-free survival; secondary endpoints were non-relapse mortality and incidence of acute and chronic GVHD. Methods: Fifty-seven patients (pts) were enrolled so far in the study and 49 are evaluable for analysis. Treatment plan consisted of high-dose R (500 mg/ms on day -6) followed by thiotepa (12 mg/kg), fludarabine (60 mg/kg) and cyclophosphamide (60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mini-methotrexate; ATG (7.5 mk/kg) was only added for pts allografted from one antigen mismatched sibling or unrelated donors. Histopathological subtypes included 24 aggressive (HG) (n= 17 diffuse large B-cell lymphomas, n= 7 mantle cell lymphomas) and 25 indolent lymphomas (LG) (n= 13 follicular lymphomas, n= 12 small lymphocytic/chronic lymphocytic leukemia). Patients were allografted from related siblings (SIB) (n= 32 matched, n=1 one single mismatched) or unrelated donors (UD) (n=11 matched, n=5 mismatched). All the pts had chemosensitive disease (n=20, 41% in complete remission) and 26 (53%) came from a failed autoSCT. Results: At a median follow-up of 13 months (range, 5–44 months), 36 pts are alive [n=27 (75%) in CR] and 13 died from any cause [n=6 for non-relapse mortality (NRM), n=7 for disease progression]. All the patients engrafted (94% had full donor chimerism at 3 months). The cumulative incidence (CI) of NRM was 13% at 1 year: 9% vs 19% for SIB and MUD (p=0.3), and 9% versus 16% for for LG and HG (p=0.3), respectively. In total only 11 of 49 pts had acute GVHD (n=8 grade II, n=3 grade III) with an estimated CI of 21% at 100 days. In the previous GITMO study the incidence was 35% with SIB only. Forty pts are evaluable for chronic GVHD with an estimated CI of 41% and 47% at 1 and 2 year, respectively (n=11 limited, n=3 extensive). Infections after engraftment requiring hospitalization or intravenous treatment were evaluable in 46 pts (n=3 excluded for early death). The overall incidence of infections was 58% (n=27) including 5 pts experienced sepsis and 10 pts pneumonia. Preliminary data on immune-reconstitution at 1 year showed: 1) low number of circulating B cells (median CD19+/ul: 129/ul) with an expansion of naive cells (IgD+, CD27-); 2) the median value of IgM was 89 mg/dl whereas IgG and IgA remained at low levels. The CI of relapse was 26% and 37% at 1 year and 2 years, respectively. In the indolent and aggressive groups, OS estimates at 2 years were 79% (95%CI, 52%-91%) and 61% (95 CI, 38%-77%) and PFS estimates were 53% (95%CI, 23%-76%) and 48% (95% CI, 27%-66%), respectively. Conclusions: The present data suggest that the administration of high-dose R is feasible and causes an unexpected reduction of the incidence of acute GVHD without increasing the NRM and the incidence of severe infections complications. Complete data evaluating the effects of R on immune reconstitution are ongoing. Disclosures: No relevant conflicts of interest to declare.

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