ALBERT

Description: Purpose Monitoring of minimal residual disease (MRD) after allogeneic stem cell transplantation (allo-SCT) by quantitative real-time PCR (qRT-PCR) of rearranged Ig- and TCR-genes may highlight patients with highest risk for relapse to whom pre-emptive treatment may be offered. Patients and Methods In the prospective phase 3 trial ALL-SCT-BFM-2003 (recruitment period 09/2003 to 09/2011; time point of analysis May 2013), MRD was assessed in bone marrow immediately on days +30, +60, +100, +200 and +365 post transplantation in 115 patients. Of these, 48 were male and 67 were female patients. All received a myeloablative conditioning regimen with TBI and VP 16. Patients received their transplant in CR2 (n=94), CR3 (n=21), CR4 (n=1) or NR (n=2). The transplantations were performed with bone marrow from matched sibling donors (MSD, n=23), matched unrelated donors (MUD, n=71) or with T-cell depleted stem cells from mismatched donors (MMD, n=21). Fifty-four patients were younger than 10 and 61 patients were older than 10 years at the time of transplant. Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD-Group and MRD results were not released to the clinicians. Results The total group of patients showed a pEFS of 0.52±0.10; cumulative incidence of relapse (CIR) and cumulative incidence of treatment related mortality (CI TRM) was 0.41±0.11 and 0.19±0.09, respectively. In 76 patients, MRD could also be assessed prior to transplant: patients who were MRD negative (n=41) had a three year pEFS of 0.62±0.04, patients with a MRD load of 1E-3 survived their disease. MRD values post transplant were analyzed as time-dependent covariates. When analyzed either for the different time points or for the highest MRD value post transplant, MRD results had always significant influence on survival. Taken the highest MRD value post transplant, probabilities of pEFS and CIR were 0.65±0.11 and 0.23±0.09 for MRD negative patients (n=72), 0.36±0.18 resp. 0.75 ±0.18 for patients with MRD

Description: Abstract 4696 Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunologic disorder caused by defects in the Fas-induced programmed cell death pathway. Impaired lymphocyte apoptosis results in gradual lymphocyte accumulation and dysregulation of lymphocyte homeostasis. ALPS patients usually suffer from persistent generalized lymphadenopathy, hepato-splenomegaly, immune-mediated cytopenias, and other autoimmune phenomena. A 15-month-old boy was diagnosed with ALPS when he presented with typical symptoms. Lab exams showed a pancytopenia, elevated serum immunoglobulin levels, a peripheral expansion of double-negative T lymphocytes of up to 40% of TCRab+ T cells and impaired lymphocyte apoptosis. Molecular analysis confirmed the diagnosis of a type Ia ALPS by identifying a heterozygous Fas gene mutation (D260H). Despite treatment with repeated pulses of high-dose methylprednisolone, intravenous immunoglobulins, and mycophenolate mofetil (MMF) to control lymphoproliferation and recurrent pancytopenia his disease progressed. At three years of age he developed numerous arterial aneurysms of the iliac, mesenterial, renal, hepatic, right middle meningeal, brachial and femoral arteries up to 2.6 cm in diameter and lymphoproliferation resulting in paraplegia and right arm paresis. Stem cell transplantation was considered, and BMT from a 9/10 matched unrelated donor (MUD) after a reduced intensity conditioning regimen (CR) with Fludarabin (150 mg/m2), Melphalan (140 mg/m2/d) and ATG (60mg/kg) was performed using 5.22 × 106 CD34+ cells/kg body weight. However, graft failure had to be diagnosed on day +27. 53 days after the first BMT a PBSCT from the same donor after myeloablative CR using Busulfan (19.2 mg/kg/d i.v.), Etoposid (30 mg/kg/d), Cyclophosphamid (120 mg/kg/d) and ATG (60mg/kg) was performed (24.5 × 106 CD34+ cells/kg bw). Again, graft failure was seen. At day +55 a third HSCT using PBSCT from another 9/10 MUD after CR with Fludarabin i.v. (160 mg/m2), Thiotepa (5 mg/kg/d), 4 Gy total body irradiation (TBI) and campath (1 mg/kg) was performed. 10.8 × 106 CD34+ cells/kg bw were given intra osseous, 9.8 × 106 CD34+ cells/kg bw were given i.v. Engraftment was slow (Leukos 980 day +35), but chimerism showed 99 % donor cells. Two years later the patient is alive and well, with persistent engraftment and good hematological and immunological function. Arterial aneurysms stopped growing and some have thrombosed. This case illustrates some interesting points. Atypical and unusually severe manifestations of ALPS forced us to perform a HSCT in this patient. In severe ALPS stem cell engraftment is difficult to achieve as previously reported in the Fas deficient lpr mouse model. One reason might be the reduced ability of cytotoxic drugs to induce apoptosis in the Fas deficient recipient T cells. Thus, recipient T cells could persist and kill donor cells resulting in graft failure or rejection. Additionally, increased FasL expression on recipient cells could induce apoptosis in Fas bearing donor stem cells as shown in lpr mice. Also, trapping of infused stem cells in the extremely enlarged liver and spleen could have played a role. A 3rd attempt was therefore designed to overcome graft resistance and proved finally successful. The use of TBI together with campath possibly induced more T cell apoptosis than chemotherapy alone. The intra osseous application probably increased engraftment efficiency by avoiding trapping of stem cells in liver and spleen and possibly by induction of tolerance by intra osseous application as described before. Disclosures: No relevant conflicts of interest to declare.

Description: A large proportion of patients with mutations in the Wiskott Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Intravenous immunoglobulin and antibiotic prophylaxis until stem cell transplantation (SCT) at an early age is the treatment of choice for classical WAS patients. For patients with XLT the optimal treatment is much less clear. Most of them reach adulthood without significant problems. However, severe complications such as infections, bleeding, autoimmune disorders and malignancies have been observed in these patients, albeit at a lower rate than in classical WAS patients. In order to provide a basis for treatment decisons in XLT patients we intended to define the natural course of disease in XLT patients and assess the probability of severe disease related complications. A retrospective survey at centers treating primary immunodeficiency patients was carried out and data were collected for patients with a documented WASP gene mutation and a WAS disease severity score of 2 or less, implicating thrombocytopenia and mild eczema and minor infections only. Data from a total of 182 patients from 12 countries could be analyzed. Median age at last follow-up was 11.2 years (range 0.4–74.6). Overall probability of survival censored for SCT was favorable in this cohort with 95%, 86% and 78% at 20, 40 and 60 years of age respectively. We did however observe a high rate of severe disease related events such as potentially life threatening infection or bleeding, autoimmune disease or malignancy. Therefore the probability to be alive without a serious event was only 66%, 45% and 29% at 20, 40 and 60 years respectively. Out of all 182 patients 13 (7%) developed severe infectious events, 3 of which were fatal. Severe bleeding episodes occurred in 23/182 (13%), 4 of which were fatal. Autoimmune disease developed in 22/182 (12%) and 9/182 (5%) were diagnosed with malignancy, 6 of whom have died. Overall and event free survival probabilities were not significantly influenced by the type of mutation or the presence of WASProtein. Patients receiving any antibiotic prophylaxis or IVIG had no survival benefit compared to others. Splenectomy, which was performed in 39/182 patients (21%), posed a significant risk to experience a severe infectious event (p

Description: The programmed death-1 (PD-1) inhibitor nivolumab has shown substantial activity in adults with relapsed or refractory Hodgkin's lymphoma (HL). Various clinical trials are currently ongoing to evaluate efficacy and safety of PD-1 blocking antibodies in other lymphoid malignancies as well. However, only limited experience has been obtained in children and adolescents so far. Here, we report the clinical course and striking response to nivolumab salvage therapy in 3 pediatric lymphoma patients. Patients of age 11, 17, and 15 years were diagnosed with classical HL (#1), mediastinal gray-zone lymphoma (#2), and diffuse large B-cell lymphoma (#3), respectively. They underwent first-line therapies according to national pediatric standard treatment recommendations. All patients achieved initial remission, but #1 and #2 relapsed soon after, #3 already during first-line therapy. Relapse in #2 presented as classical HL. Second-line therapy resulted in remission in #1 but relapse occurred again shortly after high-dose chemotherapy followed by autologous stem cell transplantation and responded poorly to further treatment. Relapses in patients #2 and #3 were already refractory to extensive second-line regimens. All patients had very poor prognosis with fast progression of disseminated disease as confirmed by FDG-PET/CT imaging. High PD-ligand 1 expression in lymphoma specimens supported the decision to initiate off-label nivolumab therapy after obtaining informed consent. Nivolumab was administered at a dose of 3 mg/kg at weeks 1 and 4 followed by biweekly courses (Ansell et al., N Engl J Med, 2015). Already following the first infusion, a remarkable improvement of clinical symptoms was observed in all individuals. Rapid responses were proven by FDG-PET/CT in week 5 after only 2 applications, demonstrating metabolic partial remission in patient #1 and already complete remission (CR) in #2 and #3. Patient #1 eventually achieved CR after 8 nivolumab administrations. Therapy was continued and follow-up imaging confirmed durable CR status in all 3 individuals. Treatment has been well tolerated and no adverse events have occurred. Patient #1 proceeded to unrelated donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) after a total of 11 nivolumab applications and remains in CR 〉4 months post allo-HSCT without significant side effects. Patients #2 and #3 are scheduled for allo-HSCT, having received 11 and 5 courses nivolumab to date. The reported cases suggest that nivolumab can be highly effective and safe in children and adolescents with different relapsed lymphoma types, refractory to previous intensive chemo- and radiotherapy. Early and sustained CR status was achieved in all 3 patients following nivolumab initiation. Our observations may encourage further clinical studies and implementation of anti-PD-1 antibodies in therapy strategies for pediatric lymphomas. Disclosures No relevant conflicts of interest to declare.

Description: Background: HLA haploidentical stem cell transplantation with T-replete grafts and post-transplant immunosuppression with high-dose cyclophosphamide after reduced intensity conditioning has evolved into an increasingly accepted method of alternative donor transplantations in adults. Reported transplantation related mortality, GVHD and relapse rates are at least comparable to those of HLA matched donor transplantations. Purpose: To assess the feasibility of this approach in children as a first or second allogeneic transplantation after myeloablative or reduced toxicity conditioning. Patients/methods: Ten consecutive transplantations in children with either malignant (n=6) or non-malignant diseases (n=4) at a single institution transplanted with unmanipulated bone marrow from parental HLA haploidentical donors were analyzed. In the malignant cohort (3 ALL, 2 AML, 1 MDS) four patients were in advanced disease status (2 NR, 2 CR3) and three had received a prior allogeneic transplantation (2 relapses, 1 rejection). Conditioning in these patients was either TBI-VP16 (n=3) or myeloablative treosulfan-based (n=3). Among the non-malignant patients (2 IL10R deficiency, 1 sickle cell disease, 1 XIAP), one had rejected a prior T-cell depleted HLA haploidentical transplantation. These patients were conditioned with alemtuzumab, treosulfan, fludarabine ± thiotepa. All patients in both groups received cyclophosphamide 14,5mg/kg on days -3 and -2. GVHD prophylaxis consisted of cyclophosphamide 50mg/kg on days +3 and +4, tacrolimus and MMF from day +5. In the absence of GvHD MMF was stopped on day +35, tacrolimus tapered from day +60 (malignant) or day+100 (non-malignant). Results: After a median follow-up of 6 months (1-25), 9 of 10 patients are fully engrafted, alive and free of disease. One patient with AML not in remission at transplantation died from pulmonary hemorrhage on day +24. He was also treated for CMV viremia pre-existing before transplantation. One ADV reactivation requiring pre-emptive treatment and no invasive fungal infections were noted in the other patients. Engraftment was recorded at a median of 17 days (neutrophils) and 26 days (platelets). Only in one patient transient acute skin GVHD (overall grade II) was observed, while no patient developed chronic GVHD. Mean CD3 counts of 310/µl, 937/µl and 1868/µl, CD4 115/µl, 291/µl and 1010/µl, CD8 176/µl, 589/µl and 802/µl and CD19 102/µl, 360/µl and 641/µl were measured on days +100, +180 and +365 respectively. Conclusion: HLA haploidentical transplantation with post-transplant cyclophosphamide appears to be a safe and promising approach with very low GVHD rates and excellent immune reconstitution in children with malignant as well as non-malignant diseases. This may be combined with myeloablative as well as reduced toxicity conditioning regimes and is a promising approach even as a second allogeneic procedure after relapse or rejection following a first allogeneic transplant. Disclosures No relevant conflicts of interest to declare.

Description: Autoimmune lymphoproliferative syndrome (ALPS) is a complex genetic disorder characterized by defective Fas apoptosis pathway, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ+ CD4- CD8- double-negative (DN) T cells. These aberrant cells express the surface molecules CD45RA and CD57 and lack expression of CCR7 and CD127, suggesting terminal differentiation or exhaustion of DN T cells. However, high eomesodermin and marginal T-bet expression and lack of killer cell lectin-like receptor G1 (KLRG1) rather point to a long-lived memory state with potent proliferative capacity. The relevance of this discrepancy, their underlying signaling pathways and the resulting functional properties remain poorly understood. Here we show that despite their terminal differentiated phenotype human ALPS DN T cells exhibit substantial mitotic activity in vivo. Notably, baseline and activation induced phosphorylation of serine-threonine kinases Akt and mTOR was markedly increased in DN T cells from ALPS patients. The mTOR inhibitor rapamycin (sirolimus) abrogated survival and proliferation of DN T cells but not of CD4+ or CD8+ T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation and abolished production of IL-10 and FasL by DN T cells. Taken together, this work uncovers the importance of mTOR signaling as a critical regulator of lymphoproliferation and accumulation of aberrant DN T cells in human ALPS and underlines the importance of therapeutic modulation of this pathway. Disclosures No relevant conflicts of interest to declare.

Description: The cure rate in pediatric acute lymphoblastic leukemia (ALL) is about 85%. Therapy failures are mainly due to relapse. Relapse rates could possibly be influenced by the anti-leukemic activity of the immune system, e.g. by the Th1/Th2 balance. It would be desirable to increase the cure rate if the immune system could be induced to participate in the elimination of leukemia cells. However, leukemia cells, especially ALL cells are poor stimulators for T cells and do not induce a Th1 response believed to be necessary for tumor cell elimination. Missing costimulatory molecules on the leukemia cells, especially CD80 and CD86, are commonly accepted as the main reason for their poor immunostimulatory activity. On the other hand, efficient costimulation does not guarantee improved cure rates. On the contrary, in a mouse model inoculation of CD86 transfected lymphoma cells led to tumor progression possibly by interaction with CD152 or induction of a Th2 response. Indeed, in an earlier study, we examined the mRNA expression of CD80 and CD86 in marrow samples of ALL patients and found an increased expression of CD86 and IL-4 in patients with a late leukemic relapse raising the possibility of a Th2 shift predisposing to relapse (Stachel et al, Eur J Med Res, 2006). It becomes increasingly clear that members of the costimulatory family other than CD80 and CD86 also influence the immune response. ICOS/ICOS ligand and PD-1/PD1 ligand both play an important role in the second step of Th2 induction. To determine whether increased or decreased expression of costimulatory molecules play a role in the pathogenesis of relapse in pediatric ALL we examined the expression of various costimulatory molecules in leukemic marrow samples in a prospective study. Samples from 49 consecutive pediatric patients with B cell precursor acute lymphoblastic leukemia (BCP ALL) were analyzed by semiquantitative RT-PCR for CD28, CD152 (CTLA-4), ICOS and ICOS ligand (B7RP-1). A total of 29 patients (60.4 %) remained relapse free and 19 (39.6 %) relapsed after a median follow up of 24.5 months (range: 6 to 50 months). Of those relapsing five patients suffered a very early relapse (VER, within 18 months from diagnosis), seven an early relapse (ER, between 18 and 30 months from diagnosis) and seven patients a late relapse (LR, later than 30 months from diagnosis). We found that in the subgroup of ALL patients experiencing a VER expression of mRNA ICOS ligand was significantly increased (2.0 +/− 0.7 (mean +/− SD relative intensity units) compared to non-relapsing patients (1.1 +/− 0.8, p=0.02). This trend was also visible in the late relapsing patient group (1.4 +/− 0.8 vs 0.9 +/− 0.6, ns). By comparative densitometry we estimated the copy number of ICOS ligand in the VER group to be 500,000 per 12,500 BM cells vs 350,000 per 12,500 BM cells in non-relapsing ALL patients. Since ICOS ligation on T-cells by ICOS ligand on B-cells appears to favor a Th2 polarization of the immune system our results could provide further evidence that a Th2 shift induced by leukemic blasts could confer an increased risk for very early ALL relapse. These data could provide a rationale for immunotherapeutic strategies aimed at strengthening a Th1 polarized immune response in the treatment for childhood BCP ALL.

Description: Background Standard myeloablative conditioning treatment prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) of children is associated with a considerable risk of severe adverse events (AEs). Previous clinical studies in adults confirmed that treosulfan-based conditioning has myeloablative, immunosuppressive and anti-neoplastic effects associated with favorable non-relapse mortality (NRM). Therefore, treosulfan-based conditioning treatment was prospectively evaluated in pediatric patients with hematological malignancies within an extended clinical phase II trial. Patients and Methods In this prospective, single-arm, open-label phase II trial we evaluated a treosulfan-based preparative regimen in pediatric patients with hematological malignancies undergoing alloHSCT. The trial was designed to assess safety and efficacy of a body surface area (BSA) adapted treosulfan dosing regimen of 10, 12 or 14 g/m2/day (according to individual BSA of ≤0.5, 〉0.5 to 1.0, or 〉1.0 m2) on Days -6 to -4. Objectives of the trial included overall survival (OS) based on Kaplan-Meier estimates, cumulative incidence (CI) of NRM and disease relapse/progression (RI). NRM was defined as the probability of dying after alloHSCT in the absence of persisting disease or previous occurrence of relapse/progression or graft failure. Moreover, the CI of acute/chronic graft versus host disease (a/cGvHD), the conditional CI of engraftment, Kaplan-Meier estimates of GvHD-free and Relapse/Progression-free Survival (GRFS) and cGvHD-free and Relapse/Progression-free Survival (CRFS), the incidence of complete donor type chimerism (defined as ≥ 95% donor cells), as well as frequencies of adverse events (AEs) until 100 days after alloHSCT were evaluated. Further, treosulfan concentration in plasma was analyzed to calculate AUC and Cmax in a subset of patients. Results Seventy pediatric patients with acute lymphoblastic leukemia (ALL [38.6%]), acute myeloid leukemia (AML, [41.4%]), myelodysplastic syndrome (MDS, [14.3%]), or juvenile myelomonocytic leukemia (JMML, [14.3%]) were enrolled between Nov-2014 and Apr-2016. The median patient age was 9.5 years (range 0-17 years) and median follow up was 12.0 months (range 11.5-17.7 months). Patients received treosulfan intravenously at a dose of 10 g/m2/day (8.6%), 12 g/m2/day (37.1%), or 14 g/m2/day (54.3%). Treosulfan was combined with fludarabine only (7.1%) or fludarabine and thiotepa (92.9%) at the investigators' discretion. The maximum conditional CI of granulocyte engraftment was 100.0% (90% CI: 97.7, 100.0). The incidence of complete donor-type chimerism at visit Day +28 was 94.2% (90% CI: 87.2, 98.0). OS at 12 months was 91.4% (90% CI: 83.9, 95.5). NRM at 12 months was only 1.4% (90% CI: 0.0, 3.8) and RI was 15.7% (90% CI: 8.6, 22.9). There was no statistical significant difference between the three dose groups with regard to any of these objectives. Grade II to IV and III to IV aGvHD were 26.1% and 8.7%, respectively. At 12 months overall cGvHD was 24.8% and moderate/severe cGvHD was 18.8%. GRFS at 12 months was 64.7% (90% CI: 54.2, 73.4) and CRFS was 66.0% (90% CI: 55.5, 74.6). The three most common CTCAE terms of at least grade III were mucositis oral (41.4%), infections and infestations - other (28.6%), and nausea (17.1%). One (1.4%) patient developed hepatic sinusoidal occlusion syndrome (grade II acc. to Jones) and recovered after 22 days. Frequencies of AEs with at least CTCAE grade III apparently correlated with increasing dose group. However, median AUC was comparable between the three different dose groups (1287 mg*hr/L [10g/ m2], 1268 mg*hr/L [12g/m2] and 1461mg*hr/L [14g/m2]) as evaluated in a subset of 58 patients. Median Cmax was also comparable between the different dose groups (628µg/mL [10g/m2], 583µg/mL [12g/m2] and 656µg/mL [14g/m2]). Conclusions The 12-month follow-up data of this phase II trial confirm that treosulfan-based conditioning with BSA-adapted dosing was safe and effective in pediatric patients with hematological malignancies. The cumulative incidence of OS and NRM compared favorably to those reported for other conditioning regimens. Treosulfan/fludarabin/thiotepa is therefore considered to be a reasonable alternative for myeloablative conditioning in this pediatric patient population. (Funded by medac GmbH, MC-FludT.17/M, EudraCT no: 2013-003604-39; ClinicalTrials.gov identifier: NCT02333058). Figure. Figure. Disclosures Kalwak: medac: Other: travel grants; Sanofi: Other: travel grants. Bader:Riemser: Research Funding; Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Gruhn:Jazz Pharmaceuticals: Honoraria. Patrick:medac: Other: Funding for EBMT conference fees and accomodation. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Corbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kremens:DSMC for industry driven clinical study: Consultancy; Miltenyi Biotec Germany: Consultancy. Vora:Pfizer: Other: Advisory board; Medac: Other: Advisory board; Novartis: Other: Advisory board; Amgen: Other: Advisory board; Jazz: Other: Advisory board.

Description: Juvenile myelomonocytic leukemia (JMML) is a rare disease in childhood which can only be cured by stem cell transplantation. The major complication is relapse in up to half of the patients. The existance and efficacy of graft-versus-leukemia (GvL) in JMML is controversial and often associated with severe graft-versus-host disease (GvHD). A 1,5 year old boy developed JMML and was transplanted from a 1 antigen mismatched UD (unmanipulated bone marrow, 8.5 Mio CD34/kg) after a CR consisting of Bu 16*1.25 mg/kg), Cy (2*60 mg/kg), Mel (1*140 mg/m2) and ATG (3*20 mg/kg). GvH prophylaxis consisted of CsA and very short MTX. The situation was further complicated by the intermittent presence of CMV, HHV-6 and EBV in the peripheral blood which was treated intermittently by intravenous ganciclovir. Engraftment occurred on day + 16. GvHD III° of the skin only developed and was treated with corticosteroids, CsA and MMF. Chimerism was complete on day +28. Beginning on day +45 an increasing autologous chimerism was detected. Therefore, immunosuppression was halted. Despite discontinuation of all immunosuppressants the autologous chimerism increased to 60–80% (d +63) and the peripheral leukocytes increased to approx 30,000/μl together with eosinophilia (d +60). Clinical signs of relapse (hepatomegaly and pulmonary obstruction) were also present. Thereafter, within a week, leukopenia and thrombocytopenia developed and the autologous chimerism decreased to 1–5%. Coinciding with the apparent GvL effect severe GvHD reappeared. Skin GvHD II–III° developed, than gut GvDH III° with massive life threatening fluid and potassium loss (day +73). In an attempt to treat both JMML and GvHD the antimetabolite purinethol 50 mg/m2 daily was given orally. Since day + 98 always an complete chimerism was observed. Gut GvHD gradually improved without further immunosuppression. The boy is now at home without evidence of disease or active GvHD more than 1 year after relapse. We speculate that in this case purinethol controlled not only the severe gut GvHD after BMT but also JMML. This antimetabolite may therefore be considered as an immunosuppressant for GvHD when malignat relapse is also present or imminent.