Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation

Storb, Rainer; Gyurkocza, Boglarka; Storer, Barry E.; Sorror, Mohamed L.; Blume, Karl G.; Niederwieser, Dietger; Chauncey, Thomas R.; Pulsipher, Michael A.; Petersen, Finn; Sahebi, Firoozeh; Agura, Edward; Hari, Parameswaran; Bruno, Benedetto; McSweeney, Peter A.; Maris, Michael B.; Maziarz, Richard T.; Langston, Amelia; Bethge, Wolfgang; Vindeløv, Lars L.; Franke, Georg‐Nikolaus; Laport, Ginna G.; Yeager, Andrew M.; Hübel, Kai; Deeg, H. Joachim; Georges, George E.; Flowers, Mary E.D.; Martin, Paul J.; Mielcarek, Marco; Woolfrey, Ann E.; Maloney, David G.; Sandmaier, Brenda M.

doi:10.1200/jco.2012.45.0247

Cited by 195 publications

(167 citation statements)

References 41 publications

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“…28,29 Indeed, there is evidence that GvHD can be associated with GvL and also with graft versus tumor effects. 7,17,30,31 The most important NK cell maturating and activating cytokine IL-15 is being evaluated in a clinical trial (NCT01727076) and could be advantageous in terms of NK cell and T cons effector function compared with IL-2, also for not inducing T reg expansion. 32,33 EWS is a suitable target for NK cells owing to reduced HLA I expression and NKG2D positivity.…”

Section: Discussionmentioning

confidence: 99%

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Schlegel

Feuchtinger

Nitschke-Gérard

et al. 2015

Bone Marrow Transplant

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Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cellmediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Schlegel

Feuchtinger

Nitschke-Gérard

et al. 2015

Bone Marrow Transplant

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“…Survival after HLA-matched sibling or unrelated donor SCT seems to be similar, 16,26,63,64 although HLA-mismatched donors (at one to two loci) result in inferior outcomes. 65,66 Alternative sources such as umbilical cord blood (UCB) and haploidentical donors seem to be effective in RIC SCT.…”

Section: Graft and Donor Sourcesmentioning

confidence: 99%

“…2,18,49,83 However, it seems that after RIC, the benefit of reduced relapse rates in the context of chronic GvHD does not consistently translate into a survival benefit due to higher mortality in older patients with chronic GvHD. 26,49 Interestingly, acute and chronic GvHD seem to increase the cost of RIC SCT to a greater extent than relapse. 84 Reduced-intensity and myeloablative regimens are associated with similar rates of infections and CMV reactivation, although early bacterial infections are less common after RIC, reflecting a shorter period of neutropenia.…”

Section: Toxicitymentioning

confidence: 99%

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Reduced-intensity conditioned allogeneic SCT in adults with AML

Reshef

Porter

2015

Bone Marrow Transplant

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AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML. ( Bone Marrow Transplantation THE RATIONALE FOR RIC IN AMLTraditional myeloablative transplants are effective in part due to a potent immunologic GVL effect independent of the conditioning regimen. The GVL response has been repeatedly demonstrated in allo-SCT 1,2 and through the use of DLI. 3,4 The ability to harness GVL yet minimize toxicity is highly relevant in AML, which is common in older patients and often incurable with chemotherapy alone. In 2013, AML was the most common indication for allo-SCT, 35% of AML transplants were in patients over age 60 and over 40% were performed with reduced-intensity conditioning (RIC) regimens (data from CIBMTR-Center for International Blood and Marrow Transplant Research).Data from animal models 5,6 and clinical observations regarding GVL activity [1][2][3][4]7 facilitated the development of RIC regimens. The success of initial attempts to use low-dose (2 Gy) TBI alone as conditioning was hindered by frequent graft rejections. The addition of fludarabine to low-dose TBI promoted engraftment with encouraging outcomes. [8][9][10][11][12] This supported a conceptual shift in allo-SCT away from dose intensity toward less myelotoxic regimens that rely on a potent GVL response. EFFICACY-IS THERE AN IDEAL CONDITIONING REGIMEN?The definition of RIC has been a moving target. The term 'reduced intensity' describes regimens characterized by lower rates of toxicities compared with myeloablative transplants. RIC regimens can be further classified as non-myeloablative when they result in minimal cytopenias. These regimens presumably have minimal or no direct effect on leukemic cells, relying solely on the GVL response. 13 The CIBMTR defines a RIC regimen ...

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“…Для пациентов с распространенными стадиями гемобластозов (n = 1092), неспособными перенести высокоинтенсивные режимы кондиционирования из-за возраста, высокого индекса коморбидности или тяжелой предлеченности, R. пред-ложили режим кондиционирования с минимальной интенсивностью (низкодозовое ТОТ ± флударабин), направленный на более точную оценку эффекта «трансплантат против опухоли» (ТПО) отдельно от влияния кондиционирования, а также выраженности РТПХ, не усиливаемой токсичностью кондициониро-вания [28]. Пятилетняя ОВ была от 25 до 60 % и за-висела преимущественно от коморбидности, группы риска заболевания и РТПХ.…”

Section: тенденции в режимах кондиционирования при аллогенной трансплunclassified

Allogeneic transplantation of hematopoietic stem cells: Perspectives and alternatives, own experience

Петрович¹,

Рукавицын²

2017

Ross. ž. det. gematol. onkol.

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Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation

Abstract: Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.

Cited by 195 publications

References 41 publications

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

Reduced-intensity conditioned allogeneic SCT in adults with AML

Allogeneic transplantation of hematopoietic stem cells: Perspectives and alternatives, own experience

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