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Desmoplastic small round cell tumors: Multimodality treatment and new risk factors (2019)
Scheer, Monika ; Vokuhl, Christian ; Blank, Bernd ; Hallmen, Erika ; von Kalle, Thekla ; Münter, Marc ; Wessalowski, Rüdiger ; Hartwig, Maite ; Sparber-Sauer, Monika ; Schlegel, Paul-Gerhardt ; Kramm, Christof M. ; Kontny, Udo ; Spriewald, Bernd ; Kegel, Thomas ; Bauer, Sebastian ; Kazanowska, Bernarda ; Niggli, Felix ; Ladenstein, Ruth ; Ljungman, Gustaf ; Jahnukainen, Kirsi ; Fuchs, Jörg ; Bielack, Stefan S. ; Klingebiel, Thomas ; Koscielniak, Ewa
Background To evaluate optimal therapy and potential risk factors. Methods Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed. Results Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse. Conclusion Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
Joint Modeling of Immune Reconstitution Post Haploidentical Stem Cell Transplantation in Pediatric Patients With Acute Leukemia Comparing CD34(+)-Selected to CD3/CD19-Depleted Grafts in a Retrospective Multicenter Study (2018)
Salzmann-Manrique, Emilia ; Bremm, Melanie ; Huenecke, Sabine ; Stech, Milena ; Orth, Andreas ; Eyrich, Matthias ; Schulz, Ansgar ; Esser, Ruth ; Klingebiel, Thomas ; Bader, Peter ; Herrmann, Eva ; Koehl, Ulrike
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34(+)-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3(+), CD3(+) CD4(+), and CD3(+) CD8(+) T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34(+)-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3(+) CD4(+) helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34(+)-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
Children and adults with Refractory acute Graft-versus-Host Disease respond to treatment with the Mesenchymal Stromal cell preparation “MSC-FFM”—Outcome report of 92 patients (2019)
Bonig, Halvard ; Kuçi, Zyrafete ; Kuçi, Selim ; Bakhtiar, Shahrzad ; Basu, Oliver ; Bug, Gesine ; Dennis, Mike ; Greil, Johann ; Barta, Aniko ; Kállay, Krisztián M. ; Lang, Peter ; Lucchini, Giovanna ; Pol, Raj ; Schulz, Ansgar ; Sykora, Karl-Walter ; Teichert von Luettichau, Irene ; Herter-Sprie, Grit ; Ashab Uddin, Mohammad ; Jenkin, Phil ; Alsultan, Abdulrahman ; Buechner, Jochen ; Stein, Jerry ; Kelemen, Agnes ; Jarisch, Andrea ; Soerensen, Jan ; Salzmann-Manrique, Emilia ; Hutter, Martin ; Schäfer, Richard ; Seifried, Erhard ; Paneesha, Shankara ; Novitzky-Basso, Igor ; Gefen, Aharon ; Nevo, Neta ; Beutel, Gernot ; Schlegel, Paul-Gerhardt ; Klingebiel, Thomas ; Bader, Peter
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
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