bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Cell Based Vaccine for the Immunotherapy of Acute and Chronic Leukemia by the Use of Autologous Dendritic Cells Loaded with Monoclonal Antibody Treated or Irradiated Leukemia Cells.
Authors: Duncan Caroline J. , Johnson Peter R.E. , Roddie Patrick H.
Published: October 2019

Dendritic cell (DC) vaccines in leukemia show promise as a novel treatment modality however to date clinical evidence of efficacy has been limited. This is likely to be as a consequence of a combination of factors, which include insufficient immunogenicity of the DC vaccine and vaccination taking place in an environment adverse for generation of effective immune responses i.e. in patients with active disease. Our study aims to generate more efficient cytotoxic T cell (CTL) responses by improving DC uptake and presentation of leukemia cells in the remission state and will be applicable to both acute and chronic leukemias. Monoclonal antibodies (MoAbs) have been used to treat malignant cells prior to co-culture with DCs to enhance cross-presentation and generation of specific CTLs. We investigated whether this approach could improve DC induction of CTL responses in comparison to DCs loaded with UVB irradiated apoptotic leukemia cells. In this in vitro study we generated dendritic cells from adherent mononuclear cells (differentiation with GM-CSF and IL-4) of patients in remission following chemotherapy for acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). The immature DCs were loaded with autologous leukemia cells from the patients’ presentation samples. The presentation leukemia cells were treated with either UVB irradiation or appropriate monoclonal antibodies (the anti-CD33 MoAb Mylotarg in AML and CML; the anti CD20 MoAb Rituximab or the anti-CD 52 MoAb Alemtuzumab in CLL). Apoptosis was assessed by Annexin/Propidium iodide labelling. Treatment of the leukemia cells by different MoAbs induced varying degrees of apoptosis. DC uptake of antibody treated or apoptotic leukemia cells was assessed by dual colour staining. Leukemia cells were stained with PKH and DCs labelled with FITC-CD80 or CD86. DC uptake was more efficient with MoAb treated cells irrespective of the degree of apoptosis induced by the MoAb. DCs were matured with TNFa for two days then co-cultured with autologous T cells for one week. T cell subsets and Regulatory T cells were assessed on the presentation and remission samples.The T cells were harvested and their cytoxicity assessed in an Interferon Gamma (IFNg) ELISPOT assay where the unmodified blasts were used as stimulators. Initial results show enhanced anti-leukemia activity in the MoAb treated group as compared to the irradiated group. A similar set up using allogeneic DCs and T cells confirmed the augmentation of CTL responses with MoAb treatment of leukemia cells.The use of MoAb in this setting shows promise for improvement in the success and applicability of DC vaccine strategies in leukemia.
Residual Lymphocytes in GM-CSF and IL-15 Differentiated Monocyte-Derived Dendritic Cells Enables Cytotoxic T Lymphocyte Responses.
Authors: Hardy Melinda Y. , Kassianos Andrew J. , Wilkinson Ray , Vulink Annelie , Hart Derek N.J. , Radford Kristen J.
Published: October 2019

We investigated the capacity of IL-15 to differentiate human dendritic cells (DC) from monocytes in the presence of GM-CSF (IL-15 MoDC) and compared them with MoDC differentiated in IL-4 and GM-CSF (IL-4 MoDC) as used in many immunotherapy protocols. IL-15 MoDC expressed higher levels of CD40 and HLA-DR and importantly, induced MART-1 specific cytotoxic T lymphocyte (CTL) responses with superior lytic capacity, when compared to IL-4 MoDC. In response to activation, IL-15 MoDC secreted high levels of IFN-γbut low or no IL-12, whereas IL-4 MoDC secreted high IL-12 but low or no IFN-γ. Using an IFN-γ blocking antibody, we demonstrated that IFN-γ production by the IL-15 MoDC did not account for the superior CTL responses induced. Despite immunoselecting monocytes to greater than 97% purity prior to DC differentiation, we noticed a small population (1–2%) of CD56+ and CD3+ lymphocytes in the IL-15 MoDC preparations that were less prominent in IL-4 MoDC differentiated from the same monocytes. Removal of the residual lymphocytes from monocytes prior to differentiation into IL-15 MoDC diminished their capacity to induce CTL but did not affect the expression of HLA-DR or CD40. These data suggest that IL-15-dependent cross-talk between the small lymphoid populations present and DC, during DC differentiation from monocytes results in superior CTL priming that is independent of IL-12 and IFN-γ. Based on these results, appropriately manufactured IL-15 MoDC preparations containing defined numbers of lymphoid cells should be considered for immunotherapy.
Utilization of ‘Rainy Day’ Autologous Peripheral Blood Stem Cells.
Authors: Wall Dominic , Yallouridis Alexander , Gambell Peter , David Ritchie , Miles Prince
Published: October 2019

High-Dose myeloablative therapy in conjunction with Autologous Peripheral Blood Stem Cell (APBSC) transplantation is an effective first line treatment in patients with haematological malignancies including Multiple Myeloma (MM) and Non-Hodgkin Lymphoma (NHL). With sufficient resources, APBSC’s can be harvested in patients during remission or consolidation treatment for subsequent transplantation if required (‘Rainy Day’ Collection). We investigated the eventual transplantation of ‘Rainy Day’ collections at our centre to assess the utilization of this strategy. We defined ‘Rainy Day’ collections as those that were not intended to be used as part of initial therapy and in general, patients were not planned to be transplanted within the 12 months following harvest. For collections that were transplanted within 12 months following harvest, ‘Rainy Day’ collections were differentiated based on the utilization intent at time of collection. Any collections infused within 3 months following harvest were excluded from the analysis. Over a 6 year period, we collected APBSC’s from 365 patients with the intent of ‘Rainy Day’ storage. Primary disease indications included NHL (45%, n=166), MM (12%, n=44), Acute Myeloid Leukaemia (AML) (8%, n=29) and Chronic Myeloid Leukaemia (CML) (7%, n=25). To date, 23% (n=84) of these ‘Rainy Day’ collections have been subsequently infused. NHL has been the most common disease requiring Rainy Day collections and has resulted in 41 subsequent transplants (24% utilization) with a median time between collection and infusion of 1.74 years (SD =1.60). Mean days until platelets > 20x109/L=15 (SD=7.0) and days until ANC > 0.5x106/L=10 (SD=1.7). Follicular Non-Hodgkin Lymphoma (fNHL) has accounted for the majority of NHL transplants (37%, 5/15), with 5 of 15 patients exhibiting transformation of fNHL into Diffuse Large B-Cell Lymphoma and an average time between collection and infusion of 2.07 years (SD 2.01). Peripheral T-Cell Lymphoma (T-NHL) has contributed to 15% (n=6/41) of transplanted NHL ‘Rainy Day’ collections with a mean time between collection and infusion being shorter at 1.53 years (SD=0.97). 23% of MM patients (n=44/202) have had APBSC’s collected for potential ‘Rainy Day’ utilization compared with 53% of NHL (n=166/309), 86% of AML (n=29/34) and 100% of CML (25/25). MM has shown to have the highest ‘Rainy Day’ APBSC utilisation with 55% (n=23/44) of patients resulting in transplantation. The average time between collection and infusion has been 2.79 years (SD=1.65) with mean days until platelets > 20x109/L=14 (SD =6.9) and days until ANC > 0.5x106/L=10 (SD=1.7). We conclude that it is clinically feasible and safe to perform ‘Rainy Day’ collections although more stringent criteria would result in a more efficient use of this resource intensive strategy.
Multivariate Analysis of Factors Influencing Stomatitis in Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Ohbayashi Yumiko , Imataki Osamu , Ohnishi Hiroaki , Miyake Minoru , Iwasaki Akinori , Ogawa Takaaki , Kitanaka Akira , Kubota Yoshitsugu , Tanaka Terukazu , Ishida Toshihiko , Nagahata Shunichiro
Published: October 2019

Purpose: Stomatitis in allogenic hematopoietic stem cell transplant (HSCT) recipients sometimes causes serious complications. Stomatitis causes disturbances in oral functioning thus diminishing quality of life (QOL) in transplant patients; these include such simple tasks such as feeding, swallowing and speaking. However, given this serious complication, little information is available regarding the prophylactic effect of oral intervention in hematopoietic stem cell transplantation (HSCT).

Methods: We retrospectively analyzed the incidence and severity of stomatitis after allogeneic HSCT with or without oral intervention among 96 consecutive patients in our hospital between January 1988 and March 2006. Inclusion criteria were

conditioning regarding both conventional (CST) and reduced-intensity regimens (RIST), donor source that included both bone marrow and peripheral blood omitting cord blood, HLA disparity eligible to one or two locus mismatched related or unrelated donor.

We used a combination following two strategies; one is cryotherapy which has applied since 2003, and another is oral health care which has been used since 2004. The incidence and severity of stomatitis was evaluated during the start of chemotherapy until day 100 after transplantation. Stomatitis was evaluated according to NCI CTCAE v3.0. ‘Cryotherapy’ is defined as the use of cold to treat an injury. Generally, an ice tip is used to make the mucosa cold. ‘Oral health care’ is defined as a prevention or treatment, including that administered by oneself, encompassing any of the immunologic, sensory, neuromuscular and structural functions of the mouth and craniofacial complex.

Results: The mean age was 42.7 years. Among 96 patients, 41 patients were treated by CST and 55 by RIST. The incidence of stomatitis was 30.9% (17/55) in RIST, which was significantly lower than the 90.2% (37/41) in CST (P < 0.001). Among these 96 patients, severe stomatitis (grade 3 to 4) was observed in 19 (46.3%) CST cases and in 6 (10.9%) RIST cases (P<0.001). The occurrence of stomatitis apparently decreased after oral health care was started. The incidence of overall grade was from 71.1% to 25.6%, and severe grade was from39.6% to 9.3%, at one year. Multiple logistic analysis revealed that both the conditioning regimen as well as the oral health care were independent risk factors for the incidence of stomatitis.

Conclusion: We concluded that although cryotherapy could not prevent oral stomatitis in patients who had undergone CST or RIST, the oral health care improved tissue damage due to an overall upgrade in oral hygiene during chemotherapy.
Thymoglobulin ® Rabbit Anti-Thymocyte Globulins (r-ATG) Induces Faster Platelet Recovery and Does Not Suppress Granulocyte Engraftment in a Non-Myeloablative Stem Cell Transplantation Setting.
Authors: Shapira Michael Y. , Resnick Igor B. , Gesundeheidt Benjamin , Bitan Menachem , Ackerstein Aliza , Samuel Simcha , Drey Liliane , Verkholevsky Yuri , Slavin Shimon , Or Reuven
Published: October 2019

Introduction: The role of anti thymocyte globulin in GVHD prevention is well established, but it is also known that anti thymocyte globulin induces leucopenia and thrombocytopenia and as such might theoretically delay engraftment. Additionally, fast platelet engraftment is a marker for good hematopoietic stem cell graft function. We have prospectively compared the effect of Thymoglobulin on engraftment of granulocytes and platelets following a single non-myeloablative conditioning protocol in a randomized study.

Methods: 28 consecutive patients undergoing SCT were conditioned with the NST protocol (I.V.fludarabine 30mg/m2/day (days −10 to −5) and I.V. busulfex (3.2 mg\kg on days −6 and −5), with or without I.V. Thymoglobulin according to randomization (days −4 to −1). Thymoglobulin dosing schedule: a cumulative dose of 7.5 mg/kg r-ATG was given with the following program 0.5 mg/kg day −4, 2.0 mg/kg day −3, 2.5 mg/kg day −2, 2.5 mg/kg day −1. Patients were followed for engraftment of leukocytes and platelets.

Results: only one patient rejected the graft (conditioned without Thymoglobulin, NS). In 4 patients underlying disease progression prevented engraftment of either ANC or platelets (2 per group). The median time to ANC engraftment was similar between the groups, 15±2.8 and 14±2.9 days for the Thymoglobulin and control groups respectively (figure 1, p=0.21). However, the median time for platelet engraftment was significantly shorter in patients receiving Thymoglobulin as part of the conditioning. Platelet recovery occurred 9.5±1.2 and 11±2.5 days for the Thymoglobulin and control groups respectively (figure 2, p=0.018).

Conclusions: in the non-myeloablative setting, Thymoglobulin induces faster platelet recovery and does not delay ANC engraftment.

Figure Figure Figure Figure
Clinical Analysis of Late-Onset Nephrotic Syndrome after Allogenic Hematopoietic Stem Cell Transplantation.
Authors: Luo Xiaodan , Liu Qifa , Ning Juan , Wei Yongqiang , Fan Zhiping , Zhang Yu , Sun Jing
Published: October 2019

Objective: To investigate the morbidity, pathology, pathogenesis and treatment of late-onset nephrotic syndrome (NS) after allogenic hematopoietic stem cell transplantation (allo-HSCT).

Methods: Late-onset NS was investigated in 167 patients with hematopoietic malignancies who survived more than 3 months after allo-HSCT from February 2001 to August 2006. Kidney biopsy and detection of serum levels of immunoglobulin (Ig), autoantibody, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were performed in patients with late-onset NS. Pathology of kidney was studied by light microscopy, immunofluorescence and transmission electron microscopy. Associations between the onset of NS with conditioning regimens, human leucocyte antigen (HLA) matching, chronic graft versus host disease (cGVHD) and cytomegalovirus infection were analyzed. Statistical analysis was performed with SPSS/PC version 13.0.

Results: Five patients were identified as late-onset NS after allo-HSCT in167 allo-HSCT patients, including 4 patients with membranous glomerulonephritis (MGN) and 1 patient with minimal change disease (MCD). The immunofluorescence of glomerular lesions revealed that the Ig of immune complex deposition were IgG in 3 patients, IgM in 1 patient and IgG/IgM double-positive in 1 patient. Electron-dense deposit can be found on epithelium and basement membrane under the transmission electron microscope. Serum levels of IFN-γ and TNF-α were markedly increased in NS patients as compared with patients without NS. Serum antinuclear antibody was positive in 2 patients and serum IgG and IgM were in high level in 2 patients, respectively. Glucocorticoid combined with cyclophosphamide (CTX) was fundamentally effective in treatment for late-onset NS. One patient got complete response, 3 got partial response and 1 was stable after the treatment. The associations of the onset of late-onset NS post-HSCT with conditioning regiments, HLA-matching, cGVHD and CMV infection had no statistical significance.

Conclusions: Glomerular histology of late-onset NS after allo-HSCT was comprised mainly of MGN and secondary MCD. The pathogenesis of late-onset NS may be related to the abnormality of humoral immunity. Glucocorticoid combined with CTX was a fundamentally effective treatment.
Chemokine Receptor Gene Polymorphisms and Severity of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from Sibling Donors.
Authors: Pullarkat Vinod , Sun Jiyao , Hong Fangxin , Nakamura Ryotaro , Cao Lan-Feng , Palmer Joycelynn , Forman Stephen J. , Senitzer David
Published: October 2019

Background: Single nucleotide polymorphisms (SNPs) and other genetic variations in various genes involved in the immune response have been variably associated with acute graft-versus-host-disease (GVHD). The interaction of chemokines with their receptors is crucial for organ-specific recruitment of immune cells. Trafficking of recipient antigen presenting cells as well as donor lymphocytes between lymph nodes and target tissues are especially important events in acute GVHD pathogenesis. In this pilot, retrospective study, we sought to examine the role of recipient and donor chemokine receptor gene polymorphisms in determining the incidence of severe acute GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from matched sibling donors.

Methods: Patient and donor samples were genotyped for the following chemokine receptor polymorphisms: CCR5 -59029 A/G, CCR2 190 A/G (V64I), CX3CR1 745 A/G (V249I) and CX3CR1 839 C/T (T280M) and CCR5Δ32. Due to the extreme rarity of homozygosity for the Δ32 deletion in CCR5, the CCR5Δ32 homozygotes and heterozygotes were grouped together for analysis. The relationship between polymorphism genotypes and acute GVHD outcomes (Grade 0 vs Grades III/IV) were evaluated.

Results: A total of 103 donor-recipient pairs were analyzed which included 58 recipients who experienced severe acute GVHD (Grades III/IV) and 45 recipients who did not develop acute GVHD (Grade 0). Compared to the wild type CCR5 allele, the presence of the CCR5Δ32 allele in the donor conferred an increased risk for severe acute GVHD (P=0.04). The odds ratio is estimated to be 6.16 (95% CI [0.73, 52.05]). Presence of CCR5Δ32 in the recipient was not associated with increased acute GVHD risk (P=0.14). For the CCR5 -59029 A/G polymorphism, there was the suggestion of a decreased trend for developing severe acute GVHD if the donor had the A/A genotype (P=0.09). A trend for an association with the incidence of severe acute GVHD was observed for the CCR2 V64I polymorphism in the recipient. (P= 0.08). Donor genotype for this polymorphism was not associated with severe GVHD (P=0.17). A trend towards increased incidence of severe GVHD was observed for the 745 A/G (V249I) polymorphism (P=0.1). No significant effect was observed for the CX3CR1 839 C/T (T280M) polymorphism in this study.

Conclusions: CCR5Δ32 polymorphism in the donor was associated with severe acute GVHD in this study. This and other functional chemokine receptor polymorphisms are potential candidates for evaluation in large prospective studies in future to precisely determine their association with acute GVHD.
Day 15 Dendritic Cell Recovery Predicts Overall Survivial after Autologous Stem Cell Transplantation in Non-Hodgkin’s Lymphoma.
Authors: Siddiqui Mustaqeem A. , Markovic Svetomir N. , Nevala Wendy K. , Morice William , Inwards David J. , Ansell Stephen M. , Micallef Ivana N. , Johnston Patrick B. , Porrata Luis
Published: October 2019

The peripheral blood absolute lymphocyte count (ALC) on day 15 after autologous stem cell transplantation (ASCT) has been shown to be an independent predictor for overall survival (OS) for many malignancies including acute myelogenous leukemia (AML), breast cancer, multiple myeloma (MM), primary systemic amyloidosis, and Hodgkin’s and non-Hodgkin’s lymphoma (NHL). A recent report (Dean et al. BMT2005; 36, 1049–1052) suggested that infused autograft dendritic cells (DC) affect survival post-ASCT in NHL. Thus, DC recovery at day 15 post-ASCT was assessed and correlated with OS. Preliminary data from an ongoing prospective study of 28 NHL patients post-ASCT are reported. Absolute DC at day 15 was analyzed by four color flow cytometry using antibodies to CD3, CD14, CD16, and CD19. In this approach lymphocytes and DCs were initially gated by their similar forward and side light scatter characteristics; DCs were then identified as cells in this gate that lacked staining for the lymphocyte antigens CD3, CD16, and CD19 and the monocyte antigen CD14. The percentage of antigen negative cells cells in the lymphocyte gate was then multiplied by the coincident peripheral blood absolute lymphocyte to determine the absolute DC count. Survival was then analyzed using the Kaplan-Meier method. With a median follow-up of 18 months, patients recovering a DC of 10 cells/μl or above experienced superior median OS versus those who did not (not reached vs 21 months, p < 0.02, Figure 1). This study shows that an immunocompetent immune system at day 15 (not only ALC recovery, but also DC recovery) correlates with survival in NHL patients undergoing ASCT.

Figure Figure
Predicting Response to Therapy for Graft-vs-Host Disease (GvHD) with a Rapid Immune Function Assay.
Authors: Anaissie Elias J. , Diaz Jose A. , Grazziutti Monica L. , Miceli Marisa H. , Fox-Cottler Michele , Barlogie Bart , van Rhee Frits
Published: October 2019

Background: GvHD following allogeneic hematopoietic stem cell transplantation (allo-HSCT) increases morbidity and mortality and is difficult to predict for. We explored the use of a novel immune function assay to determine whether an immunologic response to changes in immunosuppressive therapy for GvHD could predict clinical response.

Methods: The FDA-approved Cylex ® Immune Cell Function assay (ICF) measures the response of whole blood CD4+ lymphocytes to stimulation with phytohemagglutinin (PHA) with as read-out ATP production. The assay is quick and results are available on the same day. Use of this test in solid-organ transplant recipients demonstrated its utility in monitoring changes in immunosuppressive therapy. A retrospective analysis of the ICF assay results from allo-HSCT patients treated at our center for acute or chronic GvHD was conducted.

Results: 13 GvHD events (11 chronic, 2 acute) occurring in 8 patients between 35 and 2118 days post-transplant (682 +/− 556 d) were analyzed. At diagnosis of GvHD, the average ICF value was 425 +/− 111 ng/mL ATP. Same day white blood cell (WBC) and absolute neutrophil count (ANC) values were 10.6 +/− 3.2 x 103 cells/μL and 9.2 +/− 3.3 x 103 cells/μL, respectively. Treatment for GvHD consisted of increasing calcineurin inhibitor dose and addition of prednisone and/or other immunosuppressants. Ten GvHD events responded to therapy within 10 +/−7 days with a corresponding significant decrease of ICF values from 430 +/− 109 ng/mL to 239 +/− 130 ng/mL (p=0.002) and a decrease of WBC from 11.2 to 8.0 x103 cells/μL (p=0.027). ANC and C - reactive protein values were not statistically different (p=0.09 and p>0.5 respectively). In contrast, no significant decrease in the ICF values before and after therapy (406 to 465 ng/mL ATP) was observed for the 3 GvHD events that failed to respond to therapy.

Conclusion: These preliminary data suggest that the ICF assay is a good predictor of response of GvHD to immunosuppressive therapy and could be used to intensify immunosuppression early in non-responders.
Risk Factors for Response after Initial Therapy for Acute Graft-Versus-Host-Disease (aGVHD).
Authors: Westin Jason R. , Saliba Rima M. , de Lima Marcos , Alousi Amin , Hosing Chitra , Qazilbash Muzaffar H. , Khouri Issa F. , Shpall Elizabeth J. , Champlin Richard , Couriel Daniel R.
Published: October 2019

Introduction: Acute GVHD remains the most important early complication and limitation to allogeneic hematopoietic stem cell transplantation (HSCT). Although far from optimal, corticosteroids remain initial standard therapy with an overall response rate of 50%. Steroid resistant patients have a dismal prognosis, with mortality rates reaching 90%.

Objective: To identify the subgroup of patients that would not benefit from initial therapy with corticosteroids. Thus, accrual of these patients into clinical studies would be mandatory.

Methods: Retrospective evaluation of all (N= 287) patients who developed biopsy proven aGVHD after allogeneic HSCT at the University of Texas M. D. Anderson Cancer Center from 1998 through 2002. All patients received initial therapy for aGVHD with methylprednisolone. Prognostic factors for response (CR/PR) to initial therapy with corticosteroids were evaluated using logistic regression analysis including age, gender, donor/patient sex mismatch (F/M), donor type, cell type, intensity of conditioning regimen, diagnosis, disease status at transplant, number of prior chemotherapy regimens, number of prior autologous HSCT, CD34+ cell dose infused, time of onset of aGVHD and grade at initiation of first line therapy.

Results: At the time of first line therapy, 89/287 patients (31%) had grade I aGVHD, 141 (49%) had grade II, and 57 (20%) had grade III–IV. Overall response to first line therapy was 56% and was comparable between patients with grade I and II aGVHD. Grade III–IV aGVHD (CR/PR 39% vs. 60%, p=0.003) and hyperacute GVHD (occurring by day +14) (CR/PR 42% vs. 61%, p=0.007) were the most significant prognostic factors for failure. Sex mismatch was associated with significantly lower response rate in patients with grade III–IV (CR/PR 12% vs. 49%, p=0.02) but not in patients with grade I–II (CR/PR 61% vs. 60%, p=0.9). Failure to respond to first line therapy was the most significant predictor of non-relapse mortality at one and two years after initiation of first line therapy (p<0.001) for all GVHD grades.

Conclusions: Hyperacute GVHD and sex mismatch are significant predictors of response to first line therapy. Response to first line therapy has a strong and independent effect on survival. These factors should be integrated in prognostic scoring systems of aGVHD, which would allow identification of patients who would not benefit from standard therapeutic approaches.

Response To First Line Therapy Overall (N=287) n %CR/PR p value CR: complete remission, PR: partial remission Grade at First Line I 89 65% Reference II 141 57% 0.2 III/IV 57 39% 0.003 Grade I/II (N=230) Grade III/IV(N=57) n, %CR/PR p value n, %CR/PR p value Hyperacute GVHD Yes 73 42% 60, 48% 13, 15% No 214 61% 0.007 170, 65% 0.03 44, 45% 0.05 Donor/Patient sex mismatch Yes 73 51% 57, 61% 16, 12% No 214 58% 0.3 173, 60% 0.9 41, 49% 0.02
Outcome of Relapse after Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) - The Effect of the Underlying Disease on Survival Following Relapse.
Authors: Singhal Seema , Frankfurt Olga , Evens Andrew , Gordon Leo , Tallman Martin , Williams Stephanie , Winter Jane , Grinblatt David , Kaminer Lynne , Mehta Jayesh
Published: October 2019

We have reported that the outcome of reduced-intensity allogeneic HSCT is not affected by the underlying diagnosis (Mehta et al, ASH 2006). With an additional year’s follow-up and a minimum follow-up of 18 months, this observation continues to remain valid in a series of 91 uniformly-treated patients with hematologic malignancies (19–71 years; median 53; 22% >60 years). 29 patients had acute leukemia, 38 had lymphoma (Hodgkin/NHL) or CLL, and 24 had myeloma. Two-thirds of the patients had refractory disease. Performance status (PS) was 0 in 31%, 1 in 47%, and 2/3 in 22%. Donors (55% aged >45 years) were HLA-matched siblings (n=51), 10/10 allele-matched unrelated individuals (n=29), or 9/10 allele-matched related/unrelated individuals (n=11). The conditioning regimen comprised 100 mg/m2 melphalan with (if no prior autograft) or without (prior autograft) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched sibling donors) or tacrolimus-mycophenolate (other type of donors). G-CSF or GM-CSF were not given routinely to accelerate engraftment. Supportive care was uniform. As the figure shows, the underlying disease did not affect overall survival (OS) after HSCT.

Figure Figure

The underlying disease did not affect disease-free survival, relapse risk or transplant-related mortality. 51 of these patients relapsed. Relapsed disease was treated with immunotherapy (withdrawal of immunosuppression and/or donor cell infusion), and/or non-immune salvage treatment options. The latter included conventional chemotherapy for all 3 disease groups, monoclonal antibodies for NHL, and drugs such as thalidomide, bortezomib and lenalidomide for myeloma. Some patients with poor performance status received only supportive therapy. 43 of the 51 relapsing patients, including all with acute leukemia, died of progressive disease or complications of salvage therapy. The 8 survivors have lymphoma or myeloma, and are in remission or have stable disease. As the figure shows, OS after relapse was significantly affected by the underlying disease.

Figure Figure

Other factors affecting OS significantly after relapse were LDH and performance status. These data suggest that the outcome of patients with hematologic malignancies is generally poor if the disease relapses after reduced-intensity HSCT. However, some patients with lymphoma or myeloma can survive for prolonged periods after relapse because of effective salvage therapy options. Patients with acute leukemia fare poorly because of lack of effective salvage therapy, and exploration of strategies such as a second allograft may be appropriate for them.
Radiation, Mylotarg, and DLI for Extramedullary Relapse from AML Post-Allogeneic Transplant.
Authors: Sharma Manish , Cumpston Aaron , Craig Michael
Published: October 2019

Introduction: Extramedullary relapse of acute leukemia after hematopoietic cell transplant often occurs as granulocytic sarcomas or leukemia cutis. There is no standard of care for these patients and their prognosis is poor. We describe three patients with extramedullary relapse who were treated with a combination of radiation, gemtuzumab ozogamicin and DLI (donor leukocyte infusion).

Methods: All three patients had a diagnosis of AML, underwent induction and consolidation therapy, and then received a myeloablative TBI-based allogeneic transplant. Two patients presented with chloromas and one presented with leukemia cutis as sites of recurrence. None had evidence of bone marrow recurrence, and relapse occurred from 4 – 11 months post transplant. All three were treated with radiation therapy to the site of relapse followed by gemtuzumab ozogamicin and DLI. The radiation doses were 20 – 30 Gy, followed by gemtuzumab ozogamicin 9 mg/m2 given every two weeks for two doses. All three patients received DLI initially at 1.0 x 10-7 CD3+ cells/kg, and subsequently dose-escalated to 2.0 x 10-7.

Results: All three patients achieved complete remission. Median disease free survival has not been reached with a median follow-up of 8 months. One patient with leukemia cutis died from GVHD nine months after the first dose of DLI. The remaining two patients are alive, disease-free, and have no evidence of GVHD.

Conclusion: The combination of radiation, gemtuzumab ozogamicin, and immunotherapy with DLI may offer survival to patients who relapse with AML after allogeneic transplant.
Analysis of Mismatched Umbilical Cord Blood Transplants for Adults Patients 45 Years or Older.
Authors: Lim Seah H. , Esler Willaim V. , Zhang Yana , Zhang Jian , Burris Colleen , Townsend Mary , Periman Phillip O.
Published: October 2019

Although hematopoietic stem cell (HSC) transplants are curative for some patients with hematologic malignancies, they have been applied primarily to younger patients. Yet, hematologic malignancies are commoner in the older populations. Therefore, despite advances in HSC transplants, many patients, especially older patients, still die of their disease. Umbilical cord blood (UCB) transplants have been shown to produce comparable results to those obtained from unrelated bone marrow transplants for adults with hematologic malignancies. UCB transplants may be particularly suitable for older patients needing unrelated HSC transplants since the incidence of GVHD is lower despite the less stringent HLA-matching requirement. Furthermore, UCB procurement is fast and can be accomplished in two weeks. However, data on the applicability of UCB transplants in older adult patient is lacking. The outcome of 14 consecutive adult patients (9 males and 5 females), 45 years or older, needing HSC transplants but without matched sibling donors in a single institution was analyzed. The median age was 55.5 years (range 45–78). The median weight was 72 kg (range 60–105). The median CD34 cells infused were 2.3 x 105/kg. Four patients received one-antigen mismatched, five patients two-antigen mismatched and five patients three-antigen mismatched transplants. Conditioning regimens consisted of Bu/Cy with (n=5) or without (n=1) ATG, Flu/Mel (n=7) and BEAM (n=1). GVHD prophylaxis consisted of cyclosporin A and methylprednisone. Five patients received double UCB transplants. The diagnosis: AML (n =8; 2 untreated secondary AML, 2 primary refractory AML, 2 secondary AML in CR1, 1 secondary AML in CR2 and 1 AML in CR3 and has failed a previous autologous transplant), CML (n=3; 2 in BC and 1 in CP1), CLL (n =2; both with advanced refractory disease) and SAA due to Hep C (n=1). Despite the age of these patients, Grade I–II acute GVHD occured in 10 patients and Grade III–IV in only 2 patients. Three patients died, all from septicemia, before engraftment could be documented. Other deaths include severe GVHD (n=2), VOD (n=1), stroke (n=1), septicemia (n=1) and leukemia relapse (n=1). Five patients are alive and disease-free. As of August 1, 2007, the 5-year actuarial DFS and OS are both 31% for the group and 50% for those <65 years (Figure 1). All five patients >65 years died within 100 days of transplants. In conclusion, some older patients needing HSC transplants may benefit from mismatched UCB transplants if they are not candidates for autologous transplants and do not have HLA-matched siblings. Obviously longer follow-up is needed in these patients to better determine the long-term effect of this approach in older patients. However, further optimization of the conditioning regimen is needed for patients older than 65 years to reduce early TRM due to toxicities.

Figure Figure
Higher CD 34 Cell Doses Reduce Non Relapse Mortality (NRM) and Do Not Increase the Incidence of Graft Versus Host Disease (GVHD) Following Unrelated Donor Blood Stem Cell Transplantation (SCT).
Authors: Narayanan Sujaatha , Barnett Michael J. , Mourad Yasser R. Abou , Forrest Donna L. , Hogge Donna E. , Lavoie Julye C. , Nantel Stephen H. , Shepherd John D. , Song Kevin W. , Sutherland Heather J. , Toze Cynthia L. , Smith Clayton A. , Power Maryse , Nevill Thomas J.
Published: October 2019

Background: Higher CD34 cell doses have been shown to increase the incidence of acute (Przepiorka D et al, 1999) and extensive chronic GVHD (Zaucha et al, 2001) following HLA-matched sibling SCT. Less is known about the influence of CD 34 cell dose in the unrelated SCT setting.

Methods: A retrospective review was performed involving 81 consecutive adult patients (pts) who underwent unrelated donor G-CSF mobilised blood SCT in Vancouver between June 2000 and October 2006. NRM, relapse risk (RR) and overall survival (OAS) estimates were determined using a Kaplan-Meier technique and univariate and multivariate analyses were done to identify factors predictive of GVHD and outcome, with particular focus on cell dose administered.

Characteristics: There were 46 male and 35 female pts with a median age of 44 (range 17–58) years. Diagnoses included acute leukemia (39 pts), chronic leukemia (14 pts), lymphoma (15 pts) and other (13 pts). Conditioning was TBI-based in 80/81 pts and GVHD prophylaxis was with continuous infusion Cyclosporine and short-course Methotrexate (MTX) (15mg/m2 d +1 and 10mg/m2 d+3, d+6 and d+11). Fifty of 81 pts received >80% of the planned MTX dose. Forty three pts received SCT from a 10/10 high-resolution HLA-matched donor, 25 pts received a 1-antigen mismatched SCT, 12 pts received a 2-antigen mismatched SCT and 1 pt a 3-antigen mismatched SCT. The donor was male for 68 pts and female for 13 pts. Median CD 34 cell dose was 7.75x106 (range−9.46x104–33.6x106)/kg.

Results: The estimated 3-year NRM, RR and OAS were 39% (95%CI 25%–50%), 30% (95%CI 17%–41%) and 43% (95%CI 31%–58%), respectively. In multivariate analysis, CD 34 cell dose >7.75x106/kg was associated with faster neutrophil engraftment, p<0.001 and reduced NRM (28% vs. 49%, p=.019), but did not influence the incidence of either acute or chronic GVHD or OAS. Multivariate analysis showed that the most important predictor of grade 3–4 acute GVHD (49% vs. 22%, p=.005), NRM (65 vs. 30%, p=.006), and OAS (24% vs. 50%) was administration of >80% of the planned MTX dose. Although having a female donor predicted for an increase in NRM (p=.03), it also was associated with a decrease in RR (0/13 pts) and did not affect OAS.

Conclusion: A high CD34 cell dose in unrelated donor blood SCT is desirable in that it does not adversely influence the incidence of GVHD and is associated with faster neutrophil engraftment and a reduction in NRM. Delivery of at least 80% of the planned short-course MTX GVHD prophylaxis continues to be critical in producing a favourable outcome.
Experience with Autologous HSC Transplant in Therapy-Related MDS/AML Using Cells Harvested Prior to the Development of the Secondary Malignancy.
Authors: Costa Luciano J. , Rodriguez Vilmarie , Porrata Luis F. , Lacy Martha Q. , Elliott Michelle A. , Tefferi Ayalew , Lust John A. , Letendre Louis , Colgan Joseph P. , Gertz Morie A. , Gastineau Dennis A. , Litzow Mark R.
Published: October 2019

Background: Therapy-related MDS/AML (t-MDS/AML) is a common and devastating complication of treatment with alkylating agents and topoisomerase II inhibitors, often employed with curative intent, in standard or high-doses, in the treatment of hematological malignancies and solid tumors. Allogeneic HSC transplant is considered the standard treatment for t-MDS/AML but its applicability is limited by the unavailability of donors, comorbidities in the recipient and risk of acute and chronic graft-versus-host disease. Patients carrying diseases commonly treated with high-dose chemotherapy and autologous HSC transplant (such as multiple myeloma and non-Hodgkin lymphoma) who latter develop t-MDS/AML occasionally have stored HSC harvested prior to the diagnosis of the secondary malignancy (hereafter called early-stored HSC). The benefit of using early-stored HSC to support myeloablative therapy for the treatment t-MDS/AML is unknown.

Methods: Retrospective, single center analysis of patients with t-MDS/AML receiving myeloablative chemotherapy with or without irradiation supported with early-stored HSC.

Results: Six patients received early-stored HSC transplant for treatment of t-MDS/AML between 2000 and 2007. Median age at the time of the transplant was 57 years (range 15–71). Three patients had been primarily diagnosed with follicular lymphoma, 2 with multiple myeloma and 1 with Ewing’s sarcoma. One patient had received prior autologous HSC transplantation. Two patients developed AML, 1 patient CMML, 1 patient RCMD, 1 patient RAEB1 and 1 patient RAEB2. Median time from diagnosis of primary malignancy to HSC harvesting was 26 (2–122) months and from harvesting to development of t-MDS/AML 44 (7–79) months. Conditioning regimen was Cy/TBI in three patients, BuCy in 2 patients and Samarium + Melphalan in one patient. Five patients engrafted neutrophils and 4 patients engrafted platelets 10–34 and 13–126 days after transplant respectively. In 3/6 patients there was disappearance of the pre-transplant chromosomic abnormality (2 patients -7 and 1 patient -7 and t(1;7)). Two patients obtained hematologic CR and two patients obtained CR without full recovery of platelets. One patient died of sepsis 230 days after transplant, one died with refractory disease on day 103 after transplant and one patient is alive with recurrence of t-MDS. Three patients are alive and free of disease 7, 73 and 87 months after transplant.

Conclusion: Myeloablative conditioning followed by autologous, early-stored HSC transplant can provide prolonged survival to patients with tMDS/AML not suitable to allogeneic SCT.
Serial Serum Cytokine Measurement in a Patient with Systemic Scleromyxedema.
Authors: Devos Timothy , Meersseman Wouter , Dubois Benedicte , Goebels Jozef , Verhoef Gregor , Delforge Michel
Published: October 2019

Systemic scleromyxedema (SSME) is a generalized and rare variant of lichen myxedematosus and is characterized by cutaneous papular mucinous deposits and extracutaneous manifestations. In 80% of the cases, SSME is associated with a monoclonal gammopathy and in approximately 10% with multiple myeloma. Pulmonary, gastrointestinal, rheumatologic and severe neurologic complications have been described. Clonal plasma cells are thought to stimulate excessive fibroblast proliferation resulting in the clinical presentation of this disorder, but little is known about the cytokine-mediated crosstalk between the monoclonal plasma cells and fibroblasts. For that purpose, we have sequentially measured the serum levels of the cytokines VEGF, FGF-b, TGF-b1 and IL-6 in a 39-year old male patient diagnosed with SSME and an IgG kappa paraprotein. The patient presented with repeated generalized epileptic insults, cognitive impairment, and progressively developed thickened skin furrows at the level of the glabella. The diagnosis of SSME was histologically proven. A transient neurologic improvement was seen after plasmapheresis and dexamethason pulse therapy and stem cells were subsequently mobilized with the CAD regimen (cyclophosphamide, adriamycin, dexamethason) and readministered after high dose melphalan. The neutropenic phase was complicated by sepsis and progressive neurological deterioration, after which the decision was taken to start with thalidomide at the dose of 200 mg/d. The patient gradually improved and one year later his cognitive function has normalized and the skin lesions have disappeared. A small M-spike remains visible on serum electrophoresis. Levels of VEGF, FGF-b, TGF-b1 and IL-6 were quantified by ELISA on platelet-poor serum and were measured at diagnosis and at six and twelve months after transplantation. Compared to the high pre-treatment levels of all four cytokines, a decrease was observed during the months after transplantation and at six months.

Table 1: serum levels of VEGF, b-FGF, TGF-b1 and IL-6 in a patient with SSME before ASCT 6 months after ASCT one year after ASCT value = mean of 5 serum samples +/− SD VEGF (pg/ml) 227,87 (+/−33,3) 110,81 (+/−24,8) 189,61 (+/−13,5) b-FGF (ng/ml) 17,77 (+/−0,32) 1,93 (+/−0,29) 1,64 (+/−0,37) TGF-b1 (ng/ml) 37,94 (+/−1,21) 20,45 (+/−0,85) 18,95 (+/−0,49) IL-6 (pg/ml) 92,82 (+/−3,2) 33,2 (+/−5,3) 32,0 (+/−4,5)

One year after administration of high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT), the serum levels of FGF-b, TGF-b1 and IL-6 remain low. Remarkably, since the dose of thalidomide has been tapered because of persistent ulnar neuropathy, the serum concentration of VEGF is increasing but not reaching the pre-transplant levels. We conclude from this report that serum levels of VEGF, FGF-b, TGF-b and IL-6 follow the clinical evolution in this patient with SSME, suggesting a role for these cytokines in the pathogenesis of SSME.
High Dose Sequential (HDS) Followed by Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Salvage Treatment of Hodgkin’s Disease (HD): A Brazilian Experience.
Authors: Duarte Bruno K.L. , Valente I.S. , Vigorito Afonso C. , Aranha Francisco J.P. , Oliveira Gislaine B. , Miranda Eliana C.M. , Lorand-Metze Irene , Pagnano Katia B.B. , De Souza Carmino A.
Published: October 2019

From May 1998 to November 2006, 77 HD patients who used the regimen of high dose cyclophosphamide HD (CY) 7 or 4g/m2, methotretaxe 8g/m2 and etoposide 2g/m2 followed by AHSCT were analyzed. Their median age was 25.8 (8.8–71.5) years, 46 males and 31 females. At diagnosis 50 (65%) were stage III or IV disease, 10 (13%) had bone marrow involvement, 29 (37.7%) bulky disease and 55 (71.4%) B symptoms. Besides that, all patients were submitted to a mean of 2 (1–4) chemotherapy lives and their status were 3 (3.9%) complete remission (CR), 17 (22.1%) partial remission (PR), 57 (74%) progression disease (PD) or in non-specified sensitivity relapse. Concerning CY dose 30 (39%) received 4 g/m2 and 47 (61%) received 7 g/m2. After the HDCY 16 (20.8%) were in CR, 22 (28.6%) PR, 28 (36.3%) remained in DP and 11 (14.3%) died most in PD. After a median follow-up of 3.97 (1.13–55.9) months, 53 (68.8%) patients were submitted to AHSCT and their present status is 30 alive [18 CR, 2PR and 10 DP]; 23 dead [2 CR, 14PD and 7 related to the procedure]. Overall survival for transplanted patients was 55% in 8 years. Currently we have 33/77 (43%) alive patients, 19 CR, 3 PR, 11 PD. Overall Survival (OS) for whole group was 32%, Disease Free Survival (DFS) 64% and Progression Free Survival (PFS) 40%. Patients who were in DP or relapse prior to the HDCY (57) compared to their status after that had a significant improvement (P=0,001), their OS was 40% to CR-PR group (24) versus 16% PD group (33). In general, mortality was 44 (57%), their cause was 19 PD (43.2%), 8 (18.2%) related to HDCY, 2 (4.5%) related to HDMTX, 7 (16%) related to AHSCT, 6 (13.6%) infections, 1 (2.3%) chronic GVHD after a reduced intensity conditioning regimen transplant and 1 (2.2%) AML. Besides that, 3 patients developed MDS and 1 developed AML. In conclusion, although it had happened a significant number of toxicity related deaths, the sequence is feasible, mainly for sensitive patients and presents an acceptable response. The authors emphasize the high frequency of poor prognosis patients and occurrence of MDS/AML in 4 (5.2%) patients.
Mobilization, Harvesting and Transplantation of Peripheral Blood Stem Cells in Patients with Severe Refractory Systemic Lupus Erythematosus - A Single Center Experience.
Authors: Xiao Yi , Sun Hanyin , Zhou Jianfeng , Liu Wenli , Zhang Yicheng
Published: October 2019

The prognosis for patients with severe refractory systemic lupus erythematosus (SLE) is poor; High dose chemotherapy with hematopoietic stem cell support is a salvage treatment under investigation for these patients. In our center, 17 patients with severe refractory SLE received autologous peripheral blood stem cells transplantation (PBSCT); Peripheral blood stem cells were mobilized with cyclophosphamide 4g/m2 and granulocyte colony-stimulating factor (G-CSF) 5 μg/kg/day. Enough PBSC were collected in all patients. There’s no mobilization-related mortality, while 3 patients developed active lupus after mobilization which was controlled by slightly increasing the dosage of steroids. Following conditioning with cyclophosphamide 6g/m2 plus anti-thymocyte globulin (ATG, 20mg/kg/d, 5 days), cryopreserved PBSC (mean MNC 4.28×108/kg and CD34(+) cell 2.48×106/kg) were infused. Median ANC and platelet engraftment time were days +11 and +12 after transplantation, respectively. Treatment related complications include mucositis (14/17), infection (12/17), liver malfuction (10/17), edema or/and heart failure (3/17), renal failure (2/17), bleeding (5/17); One patient died from cerebral hemorrhage. Median follow-up is 22 months (9–28 months); All the patients improved with the SLEDAI score reduced from 25.2±6.6 before to 9.7±1.2 3 months after transplantation; Steroids were stopped or maintained at very low dose (equal to 5 to 7.5 mg/d predinisone). One patient had overt lupus relapse 8 months following transplant Conclusions Mobilization, harvesting and transplantation of peripheral blood stem cells in patients with severe refractory systemic lupus erythematosus is safe; The short-term result of the approach is effective in this group of patients; More patients needed to enroll a control study to validate the role of high-dose chemotherapy/PBSCT as the salvage treatment for severe SLE.