Outcome of Allogeneic Transplantation for Mature T-cell Lymphomas: Impact of Donor Source and Disease Characteristics

Mature T-cell lymphomas constitute the most common indication of allogeneic hematopoietic cell transplantation (allo-HCT) in lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas, relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma-NOS (PTCL-NOS) between 2008 and 2018. HCT platforms compared were post-transplant cyclophosphamide-based haploidentical (haplo-) HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in-vivo T-cell depletion (MUD TCD+), and MUD HCT without TCD (MUD TCD-). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included non-relapse mortality (NRM), and relapse/progression incidence (RI). 1942 patients were eligible (haplo-HCT 237; MSD 911; MUD-TCD+ 468; MUD TCD- 326). Cohorts were comparable for baseline characteristics except higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. On univariate and multivariate comparisons, OS and PFS, RI, and NRM were not significantly different between haplo-HCT, MSD, MUD-TCD+, and MUD-TCD- cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%; and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared to PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma. Outcomes of haplo-HCT were comparable to that of matched donor allo-HCT.

A Review of Cyclophosphamide-Induced Transplantation Tolerance in Mice and Its Relationship With the HLA-Haploidentical Bone Marrow Transplantation/Post-Transplantation Cyclophosphamide Platform

The bone marrow transplantation (BMT) between haplo-identical combinations (haploBMT) could cause unacceptable bone marrow graft rejection and graft-versus-host disease (GVHD). To cross such barriers, Johns Hopkins platform consisting of haploBMT followed by post-transplantation (PT) cyclophosphamide (Cy) has been used. Although the central mechanism of the Johns Hopkins regimen is Cy-induced tolerance with bone marrow cells (BMC) followed by Cy on days 3 and 4, the mechanisms of Cy-induced tolerance may not be well understood. Here, I review our studies in pursuing skin-tolerance from minor histocompatibility (H) antigen disparity to xenogeneic antigen disparity through fully allogeneic antigen disparity. To overcome fully allogeneic antigen barriers or xenogeneic barriers for skin grafting, pretreatment of the recipients with monoclonal antibodies (mAb) against T cells before cell injection was required. In the cells-followed-by-Cy system providing successful skin tolerance, five mechanisms were identified using the correlation between super-antigens and T-cell receptor (TCR) Vβ segments mainly in the H-2-identical murine combinations. Those consist of: 1) clonal destruction of antigen-stimulated-thus-proliferating mature T cells with Cy; 2) peripheral clonal deletion associated with immediate peripheral chimerism; 3) intrathymic clonal deletion associated with intrathymic chimerism; 4) delayed generation of suppressor T (Ts) cells; and 5) delayed generation of clonal anergy. These five mechanisms are insufficient to induce tolerance when the donor-recipient combinations are disparate in MHC antigens plus minor H antigens as is seen in haploBMT. Clonal destruction is incomplete when the antigenic disparity is too strong to establish intrathymic mixed chimerism. Although this incomplete clonal destruction leaves the less-proliferative, antigen-stimulated T cells behind, these cells may confer graft-versus-leukemia (GVL) effects after haploBMT/PTCy.

Efficacy and safety of intravesical fibrin glue instillation for management of patients with refractory hemorrhagic cystitis: 12-months results. A promising therapy for hemorrhagic cystitis

Objectives: Fibrin glue (FG) endo-vesical application seems to be a promising therapy for hemorrhagic cystitis (HC). We aimed to evaluate efficacy and safety of FG instillation in patients with HC. Methods: Patients with HC not responsive to conventional treatments (bladder irrigation, catheterization, blood transfusions, hyperhydration and endoscopic coagulation) were treated with FG endo-vesical instillation (April 2017- December 2018). FG was prepared from 120 mL of patient blood with the Vivostat® system. After standard cystoscopy, bladder was insufflated with carbon dioxide (CO2) according to bladder compliance and autologous FG was applied to bladder wall and bleeding sites. Results: Ten patients included with grade 2 or higher HC secondary to bone marrow graft for hematological diseases (30%) or to actinic cystitis caused by prostate cancer radiotherapy (RT) (70%). The median HC onset time after RT was 4.8 (IQR 3.9- 6.3) years and 35 (IQR 27.5-62.5) days after hematopoietic stem cell transplantation (HSCT). Five patients had a complete response after one treatment, three patients had clinical response (grade < 2 hematuria, amelioration of symptoms), one of them required catheterization and bladder irrigation. One patient required a second instillation of FG achieving a clinical response. No adverse events related to the procedure were recorded, however one patient died for causes not related to the procedure. Median Interstitial Cystitis Symptoms Index was 13.0 (IQR 11.0-15.0) pre-operatively and 4.0 (IQR 2.0-5.0) post-operatively. Conclusions: Our study showed that, even in hematological patients, autologous FG instillation maybe a safe, repeatable and effective treatment modality in patients with refractory HC.

Maxillary reconstruction using tunneling flap technique with 3D custom-made titanium mesh plate and particulate cancellous bone and marrow graft: a case report

Background Reconstructive surgery is often required for tumors of the oral and maxillofacial region, irrespective of whether they are benign or malignant, the area involved, and the tumor size. Recently, three-dimensional (3D) models are increasingly used in reconstructive surgery. However, these models have rarely been adapted for the fabrication of custom-made reconstruction materials. In this report, we present a case of maxillary reconstruction using a laboratory-engineered, custom-made mesh plate from a 3D model. Case presentation The patient was a 56-year-old female, who had undergone maxillary resection in 2011 for intraoral squamous cell carcinoma that presented as a swelling of the anterior maxillary gingiva. Five years later, there was no recurrence of the malignant tumor and a maxillary reconstruction was planned. Computed tomography (CT) revealed a large bony defect in the dental-alveolar area of the anterior maxilla. Using the CT data, a 3D model of the maxilla was prepared, and the site of reconstruction determined. A custom-made mesh plate was fabricated using the 3D model (Okada Medical Supply, Tokyo, Japan). We performed the reconstruction using the custom-made titanium mesh plate and the particulate cancellous bone and marrow graft from her iliac bone. We employed the tunneling flap technique without alveolar crest incision, to prevent surgical wound dehiscence, mesh exposure, and alveolar bone loss. Ten months later, three dental implants were inserted in the graft. Before the final crown setting, we performed a gingivoplasty with palate mucosal graft. The patient has expressed total satisfaction with both the functional and esthetic outcomes of the procedure. Conclusion We have successfully performed a maxillary and dental reconstruction using a custom-made, pre-bent titanium mesh plate.

Allogeneic Transplantation for Lymphoid Malignancies with Fludarabine and Melphalan Conditioning and Different Donor Types

Introduction: Allogeneic hematopoietic stem cell transplantation (ASCT) remains a curative treatment for patients with advanced lymphomas. Haploidentical donors (HID) have recently extended transplantation for patients without HLA matched donors. Fludarabine (F) with melphalan (M) 140mg/m2 is the current standard of care conditioning regimen for ASCT. We hypothesized that progression-free survival (PFS) of patients with HID is comparable to that of HLA matched transplants, and that lower doses of melphalan (100mg/m2) are equally effective for these patients. Here, we analyzed outcomes of all lymphoma patients who received ASCT from different donors with FM conditioning at our institution between 09/2009-01/2018. Methods: A total of 186 pts (63 matched related, MRD, 98 matched unrelated, MUD and 25 HID) were included. 30 patients had chronic lymphocytic leukemia (CLL), 54 Hodgkin lymphoma (HL) and 77 Non-Hodgkin lymphoma (NHL). The median follow-up was 57 (range 3-101) months. Patients received F160mg/m2 with M140mg/m2 (FM140) or 100mg/m2 (FM100). FM100 regimen was used in older patients/significant comorbidities. Thiotepa 5mg/kg or TBI 200cGy was added to HID transplants. All matched transplants received standard graft-versus-host disease (GVHD) prophylaxis (tacrolimus + methotrexate +/-ATG for MUDs), while HID group received PTCy-based GVHD prophylaxis. The cumulative incidence (CI) of non-relapse mortality (NRM), disease progression, and GVHD was estimated accounting for competing events. Regression analysis accounting for competing events was used to evaluate predictors of outcomes. Results: Patients' characteristics were well balanced in donor groups except for advanced stage 3-4 disease (HID 77% vs MRD 51%, p=0.03), use of FM100 regimen (HID 64% vs. MUD 11% vs. MRD 10%, p<0.001) and bone marrow graft (HID 84% vs. MUD 36% vs. MRD 2%, p<0.001) (Table 1). Engraftment was similar in HID, MUD and MRD (92%, 89% and 98%, respectively; p=0.7). The CI of grade III-IV aGVHD at 6-months in HID (reference), MUD and MRD was 4%, 14% (p=0.2) and 8% (p=0.5), and the 3-year cGVHD were 5%, 16% (p=0.2) and 26% (0.09), respectively. The 3-year relapse for the HID (reference), MUD and MRD groups was 15%, 21% (p=0.4) and 39% (p=0.04), respectively. The corresponding CI of NRM was 31%, 32% (p=0.9), and 10% (p=0.02). The 3-year PFS was equivalent in the 3 donor groups at 49% (HID, reference), 44% (MUD, HR=1.2, p=0.6), and 46% (MRD, HR=1.1, p=0.8). Similarly, overall survival (OS) did not differ with respective OS of 52% (HID, reference), 54% (MUD, HR=1.04, p=0.9), and 67% (MRD, HR=0.6, p=0.2) in the 3 groups. The 3-year GVHD-relapse free survival in HID (reference), MUD and MRD groups was 39%, 31% (p=0.3) and 24% (p=0.2) respectively. Patients receiving FM100 were older (median 57 vs. 46 years, p<0.01), more likely to receive HID transplant (48% vs 6%, p<0.01) and a bone marrow graft (55% vs 25%, p=0.01), and less likely (12% vs 35%, p=0.01) to be treated for HL. On univariate analysis, FM100 regimen showed a trend for improved PFS (HR=0.7, p=0.3) and less relapse (HR=0.4, p=0.1) compared to FM140 regimen with similar NRM (HR=0.9, p=0.8) and OS (HR=0.9, p=0.7). The 3-year PFS and OS for FM100 vs. FM140 was 57% vs 43%, and 64% vs 58%. In multivariate analysis (MV), factors associated with unfavorable PFS were NHL (HR=1.9, p=0.002) and >3 chemotherapy regimens (HR=1.8, p=0.01) received prior to transplant. Including donor type and melphalan dose in MV analysis did not alter these results. Conclusions: HID transplants have lower relapse rates and higher NRM comparing with MRDs, while no significant differences were seen comparing with MUDs, and similar survival compared with HLA matched transplants in patients with lymphoma receiving FM-based conditioning regimen. Our results suggest that FM100-based conditioning, which was used primarily in older individuals, is equivalent to FM140 and could be used as prefered standard conditioning regimen for ASCT for patients with lymphoma. Controlled studies are need to compare FM100 with FM140 conditioning and to evaluate PTCY-based GVHD prophylaxis in HLA matched transplants. Disclosures Oran: ASTEX: Research Funding; AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding. Shpall:Affirmed GmbH: Research Funding. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.