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Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.

Management of Richter transformation (RT) is particularly challenging, with survival estimates <1 year. We report on outcomes of 66 RT patients undergoing allogeneic-HCT (allo-HCT) between 2008 and 2018 registered with the EBMT. Median age at allo-HCT was 56.2 years (interquartile range (IQR), 51.3–63.1). Median time from RT to allo-HCT was 6.9 months (IQR, 4.9–11) and 28 (42.4%) were in complete remission (CR). The majority underwent reduced intensity conditioning (66.2%) using peripheral blood derived stem cells. Eighteen (27.3%) patients had a matched sibling donor, 24 (36.4%) a matched unrelated donor and the remaining were mismatched. Median follow-up was 6.6 years; 1- and 3- year overall and progression free survival (PFS) (95% CI) was 65% (54–77) and 39% (27–51) and 53% (41–65) and 29% (18–40), respectively. Patients in CR at time of allo-HCT had significantly better 3-year PFS (39% vs.21%, p= 0.032). Cumulative incidences of grade II–IV acute graft versus host disease (GVHD) at day +100 was 41% (95% CI 29–53) and chronic GVHD at 3 years was 53% (95% CI 41–65). High rates of non-relapse mortality (NRM) were observed; 38% (95% CI, 26–50) at 3 years. Although potentially curative, approaches to reduce considerable NRM and chronic GVHD rates are required.

The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p< 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p= 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). A new definition for diagnosis, and a severity grading system for SOS/VOD in adult patients, was reported a few years ago on behalf of the European Society for Blood and Marrow Transplantation (EBMT). The aim of this work is to update knowledge regarding diagnosis and severity assessment of SOS/VOD in adult patients, and also its pathophysiology and treatment. In particular, we now propose to refine the previous classification and distinguish probable, clinical and proven SOS/VOD at diagnosis. We also provide an accurate definition of multiorgan dysfunction (MOD) for SOS/VOD severity grading based on Sequential Organ Failure Assessment (SOFA) score.

In this registry-based study we retrospectively compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with acute lymphoblastic leukemia (ALL) following conditioning with total body irradiation (TBI) combined with either cyclophosphamide (Cy) or fludarabine (Flu). TBI 12 Gy + Cy was used in 2105 cases while TBI 12 Gy + Flu was administered to 150 patients in first or second complete remission. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with a reduced risk of relapse (HR = 0.69, p= 0.049) and increased risk of grade 2–4 acute graft-versus-host disease (GVHD, HR = 1.57, p= 0.03) without significant effect on other transplantation outcomes. In a matched-pair analysis the use of TBI/Cy as compared to TBI/Flu was associated with a significantly reduced rate of relapse (18% vs. 30% at 2 years, p= 0.015) without significant effect on non-relapse mortality, GVHD and survival. We conclude that the use of myeloablative TBI/Cy as conditioning prior to allo-HCT for adult patients with ALL in complete remission is associated with lower risk of relapse rate compared to TBI/Flu and therefore should probably be considered a preferable regimen.

The role of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in the treatment of myeloma (MM) patients with severe and/or dialysis-dependent renal impairment remains uncertain. We report on the outcomes of 110 patients (median age 57 years) who had become dialysis-dependent pre-ASCT and who underwent a first ASCT between 1997 and 2017. Sixty-three (57%) patients had light chain MM. All patients required dialysis (94% hemodialysis and 6% peritoneal). Forty-four of 71 (62%) patients received bortezomib-based induction regimens and 42 (39%) patients had achieved at least a very good partial response (VGPR) pre-ASCT. Melphalan dosing was as follows: ≤140 mg/m2(82%), and >140 mg/m2(18%). The median PFS after ASCT was 35 months (95% CI: 21.5–42.2) and the median OS 102 months (95% CI: 70.4–129.1). At 1, 2, and 5 years after ASCT, 8% (95% CI 3–14%), 13% (6–20%), and 20% (12–29%) of patients, respectively, had achieved dialysis independence. In multivariate analyses of OS and PFS including age at ASCT, response at ASCT, and year of ASCT, younger age at ASCT and better response at ASCT (CR/VGPR/PR vs. MR/SD/progression) were significantly associated with better OS and PFS.

Autologous hematopoietic cell transplantation (auto-HCT) may be performed in multiple myeloma (MM) patients relapsing after a previous auto-HCT. For those without an adequate dose of stored stem cells, remobilization is necessary. This retrospective study included patients who, following disease relapse after the first auto-HCT(s), underwent stem cell remobilization and auto-HCT performed using these cells. There were 305 patients, 68% male, median age at salvage auto-HCT was 59 years. The median time to relapse after the first-line penultimate auto-HCT(s) was 30.6 months, the median follow-up after salvage auto-HCT 31 months. The 2- and 4-year non-relapse mortality (NRM) after the salvage auto-HCT was 5 and 9%, the relapse incidence 56 and 76%, respectively. Overall survival (OS) after 2 and 4 years was 76 and 52%, progression-free survival (PFS) 39 and 15%. In multivariable analysis an increasing interval between the penultimate auto-HCT and relapse was associated with better OS and PFS, later calendar year of salvage auto-HCT with better OS. In conclusion, salvage auto-HCT performed with cells remobilized after a previous auto-HCT was associated with acceptable NRM. The leading cause of failure was disease progression of MM, which correlated with a shorter interval from the penultimate auto-HCT to the first relapse.

Whether to choose Haploidentical (Haplo) or one-antigen mismatched unrelated donor (1Ag-MMUD) hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) remains an unanswered question. We compared PTCy- Haplo-HCT to PTCy-1Ag-MMUD-HCT for acute myeloid leukemia (AML) in complete remission (three groups: 1Ag-MMUD using peripheral blood (1Ag-MMUD-PB; n= 155); Haplo using bone marrow (Haplo-BM; n= 647) or peripheral blood (Haplo-PB; n= 949)). Haplo-BM and Haplo-PB had a higher non-relapse mortality (NRM) compared to 1Ag-MMUD-PB (HR 2.28, 95% CI 1.23–4.24, p< 0.01; HR 2.65, 95% CI 1.46–4.81, p< 0.01, respectively). Haplo groups experienced a lower leukemia-free survival (LFS) compared to 1Ag-MMUD-PB (Haplo-BM: HR 1.51, 95% CI 1.06–2.14, p= 0.02; Haplo-PB: 1.47, 95% CI 1.05–2.05, p= 0.02); overall survival (OS) was also lower in Haplo-HCT (Haplo-BM: HR 1.50, 95% CI 1.02–2.21, p= 0.04; Haplo-PB: HR 1.51, 95% CI 1.05–2.19, p= 0.03). No differences were observed for graft-versus-host/relapse-free survival (GRFS) and relapse incidence (RI). Haplo-BM was associated with a lower risk of grade III-IV acute graft-versus-host disease (GVHD) (HR 0.44, 95% CI 0.24–0.81; p< 0.01), while no statistical differences were observed between groups for grade II-IV aGVHD and for cGVHD. Use of PTCy in 1Ag-MMUD-HCT is a valid alternative to consider when using alternative donors. Larger analysis of 1Ag-MMUD versus Haplo-HCT are warranted.

Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n= 117) and thiotepa + iv. busulfan + fludarabine (TBF, n= 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p= 0.03). There was a tendency towards reduced incidence of relapse after TBF (p= 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p= 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p= 0.009) but an increased risk of relapse (HR = 2.59, p= 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all 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 not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, 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 with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

Non-T-cell depleted haploidentical hematopoietic cell transplantation (Haplo-HCT) is a unique transplantation setting in which several donors are available. We assessed the impact of donor kinship on outcome of Haplo-HCT with post-transplantation cyclophosphamide in a cohort of 717 acute leukemia patients. We compared sibling with parent donors in patients ≤45 years, and child with sibling donors in patients >45 years. Donor kinship was not associated with worse outcomes in multivariate analysis. For patients ≤45 years, the hazard ratio (HR) for leukemia-free survival (LFS), overall survival (OS), relapse incidence (RI), and chronic graft-versus-host disease (cGVHD) was 0.87 (p= 0.75), 1.19 (p= 0.7), 0.52 (p= 0.19), and 0.99 (p= 0.97) for parents versus siblings, respectively, and for patients >45 years the HR was 0.93 (p= 0.8), 0.98 (p= 0.94), 1.3 (p= 0.53), and 0.98 (p= 0.95) for children versus siblings, respectively. Univariate incidence of acute GVHD grade II-IV was significantly higher in patients transplanted from siblings versus children (p= 0.002). Factors associated with inferior outcome were advanced disease and earlier transplant. In patients ≤45 years, acute lymphocytic leukemia and peripheral blood stem cell graft were additional prognostic factors for OS. We did not find a significant impact of donor kinship on transplantation outcome when analyzing by age group (≤45 and >45 years).

Donor lymphocyte infusion (DLI) is a treatment option to prevent or treat relapse after allogeneic hematopoietic cell transplantation (HCT). We here report data for 173 patients who received one or multiple DLIs after haploidentical-HCT with post-transplant cyclophosphamide (PTCY) at 47 EBMT centers from 2009 to 2018. Indication for DLI was: prophylactic for 59 (34.3%), preemptive for 20(11.6%), and therapeutic for 93(54.1%). For the prophylactic group, the median number of DLIs was 1 (IQR:1–2.5) with a median first dose of 0.1 × 106CD3+ T cell/kg, for the preemptive 2 (IQR:1–3) with 0.5 × 106CD3+ T cell/kg, for the therapeutic 1 (IQR:1–3) with 1 × 106CD3+ Tcell/kg, respectively. OS after first DLI was 61% (46–75%) for prophylactic, 40% (19–61%) for preemptive, and 22% (13–31%) for therapeutic. CI of II-IV aGVHD and cGVHD was 17% (7–27%) and 53% (40–67%) for the prophylactic, 20% (2–38%) and 21% (3–39%) for the preemptive, 17% (9–24%) and 24% (15–33%) for the therapeutic group, respectively. Our data show great variability in the indications and modalities of DLI across responding EBMT centers. Survival rates remain relatively low in patients with active disease. While the cumulative incidence of aGVHD appears acceptable, we showed a high incidence of cGVHD in the prophylactic group, compared with preemptive and therapeutic DLI. These data should be investigated further in prospective clinical trials.

Measurable residual disease (MRD) assessment before allogeneic hematopoietic cell transplantation (HCT) may help physicians to identify a subgroup of patients at high risk of relapse for de novo acute myeloid leukemia (AML) but its relevance among patients affected by secondary AML (sAML) is still unknown. We assessed the impact of MRD among 318 adult patients with sAML who received an allogeneic HCT in first complete remission. At the time of HCT, a total of 208 (65%) patients achieved MRD negativity, while 110 (35%) had positive MRD. 2-year overall survival (OS) was 58.8 % (95% CI 52.2–64.9) with leukemia-free survival (LFS) of 50.0 % (95% CI 43.7–56.1), relapse incidence of 34.2% (95% CI 28.4–40.1) and non-relapse mortality (NRM) of 23.3 % (95% CI 19–27.7) for the entire cohort. In multivariate analysis, HCT recipients with KPS ≥ 90 experienced less disease recurrence (HR 0.61, 95% CI 0.4–0.94) with better LFS (HR 0.63, 95% CI 0.44–0.89) and OS (HR 0.58, 95% CI 0.39–0.86). There were no differences in major clinical endpoints between patients with MRD-positive and MRD-negative status at the time of HCT. Pre-transplantation assessment of MRD was not informative on post-HCT outcomes in this retrospective registry-based analysis among patients affected by sAML.

While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N= 168; ATG N= 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p< 0.00017); and CI of relapse was 23% vs 25% vs 39% (p< 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p= 0.009) respectively; and GRFS was 21% vs 28% and 20% (p= 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.

Cyclophosphamide is frequently substituted with fludarabine (Flu) in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to compare retrospectively, total body irradiation (12 Gy) plus Flu (FluTBI12) versus busulfan (Bu) plus Flu (FB4) as a myeloablative conditioning before allo-HCT in patients with acute myeloid leukemia (AML). Out of 3203 patients who met the inclusion criteria, 109 patients treated with FluTBI12 and 213 treated with FB4 were included in a final matched-pair analysis. In both groups, median patient age was 41 years, first or second complete remission (CR1/CR2) proportion was 78%/22%, allo-HCT from an unrelated donor was performed in 78% of patients. The probabilities of leukemia-free survival and overall survival at 2 years in FluTBI12 and FB4 groups were 65% vs. 60% (p= 0.64) and 70% vs. 72% (p= 0.87), respectively. The cumulative incidence of relapse was 19% vs. 29% (p= 0.11), while non-relapse mortality was 16% vs. 11%, respectively (p= 0.13). There were no statistical differences in both acute and chronic graft-versus-host disease (GVHD) incidence. The probability of GVHD-free, relapse-free survival (GRFS) was 49% for both groups. FluTBI12 and FB4 are comparable myeloablative regimens before allo-HCT in AML patients transplanted in CR1 and CR2.

The use of haplo-HCT with posttransplant cyclophosphamide (PT-Cy) is a new standard in the treatment of hematological diseases. A paucity of data exists on risk factors for engraftment failure in haplo-HCT with PT-Cy. We analyzed 1939 adults with acute myeloid leukemia (AML) who received a first haplo-HCT from 2010 to 2019. Status at haplo-HCT was first complete remission (CR1) in 72.5% of patients, secondary AML was reported in 9.9%. Median follow-up was 24.4 months and median age at haplo-HCT was 51 years. Stem cell source was bone marrow (BM) in 42% and peripheral blood stem cell (PBSC) in 58%, and 64% of patients received a myeloablative conditioning (MAC) regimen. Cumulative incidence of primary graft failure (GF) was 6%; GF was reported in 110 patients and 54 died before day +30 with no sign of cell recovery. Overall, 33 patients underwent a second HCT in a median time of 45 days and 13 were alive at last follow-up, the 2-year overall survival (OS) after second HCT being 32.4%. In multivariate analysis, factors independently associated with the risk of nonengraftment were: secondary AML (HR 1.30, p= 0.003), use of RIC (HR 1.22, p< 0.001), and use of BM (HR 1.21, p< 0.001). At 2 years, leukemia-free survival (LFS) and OS for the entire population was 55.2% (95% CI: 52.6–57.6) and 60.9% (95% CI: 58.4–63.3), respectively. Incidence of GF after haplo-HCT with PT-Cy is lower than reported T-cell-depleted haplo-HCT. Optimization of conditioning regimen and graft source should be considered for reducing the risk of GF in haplo-HCT recipients using PT-Cy.

Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed multiple myeloma.

•TBI-based MAC was associated with lower NRM in the setting of haplo-HCT with PTCy.•TBI-based MAC resulted in better LFS in patients with ALL undergoing haplo-HCT.•There was no difference in relapse, OS, or GRFS between TBI- and CT-based MAC.

The ideal stem cell graft source remains unknown in haploidentical haematopietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide (PTCy). This study compared outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for haplo-HCT in acute lymphoblastic leukemia (ALL). A total of 314 patients with ALL (BM—157; PB—157) were included in this study. The cumulative incidence of engraftment at day 30 was higher in the PB group compared with BM (93% vs. 88%, p< 0.01). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were not significantly different between the study cohorts. In the multivariate analysis, there were tendencies toward a higher incidence of grade II–IV acute GVHD (hazard ratio (HR) = 1.52, p= 0.07), chronic GVHD (HR = 1.58, p= 0.05), and nonrelapse mortality (NRM) (HR = 1.66, p= 0.06) in patients receiving PB versus BM graft, respectively. The use of PB grafts was associated with lower leukemia-free survival (LFS) (HR = 1.43, p= 0.05), overall survival (OS) (HR = 1.59, p= 0.02), and GVHD-free, relapse-free survival (GRFS) (HR = 1.42, p= 0.03) compared with BM grafts. There was no difference in relapse incidence (HR = 1.23, p= 0.41) between the study groups. In conclusion, use of BM graft results in better survival after haplo-HCT with PTCy in patients with ALL, compared with PB stem cell graft.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). While SOS/VOD may resolve within a few weeks in the majority of patients with mild-to-moderate disease, the most severe forms result in multiorgan dysfunction and are associated with a high mortality rate (>80%). Therefore, careful surveillance may allow early detection of SOS/VOD, particularly as the licensed available drug is proven to be effective and reduce mortality. The aim of this work is to propose an international consensus guideline for the treatment and prevention of SOS/VOD in adult patients, on behalf of an international expert group.

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.

Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma.

Hematopoietic cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants done in Europe and associated countries continues to rise with 45,418 HCT in 41,100 patients [(17,155 allogeneic (42%) and 23,945 autologous (58%)] reported by 683 centers in 50 countries in 2017. Main indications were myeloid malignancies 10,147 (25%; 96% allogeneic), lymphoid malignancies 26,488 (64%; 19% allogeneic), solid tumors 1,607 (3.9%; 2% allogeneic), and nonmalignant disorders 2,667 (7%; 81% allogeneic). Trends in donor choice seen before continue, with growing numbers of haploidentical HCT and decreasing use of cord blood. Of interest is that after many years of continued growth, the number of patients receiving an allogeneic HCT for marrow failure is decreasing slightly (p< 0.001). Such a change may be explained by the use of thrombopoietin analogs in aplastic anemia patients. Other nonmalignant indications, however continue to grow, most importantly HCT for hemoglobinopathies by 36%, equally for thalassemias and sickle cell disease. Non-HCT cell therapies have increased by 28% since 2015 and genetically modified T cells is type of cell therapy with the fastest growth. These annual reports reflect current activity and trends and are useful for health-care planning.

INTRODUCTION

Background

Background:T-cell acute lymphoblastic leukemia (T-ALL) predominantly affects individuals in late childhood and young adulthood and historically had high mortality rates. The outcome of Pediatric inspired chemo protocols in the T-ALL have improved in the past years due to the advancement in treatment and supportive care but the data is less mature, although adult patients still face challenges. Limited studies have directly explored the impact of patient- and transplant-related factors on post-transplant outcomes in adult T-ALL patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Allogeneic Stem Cell Transplantation for Relapsed and/or Refractory Hodgkin Lymphoma: A Multicenter Real World Experience

Background:Ide-cel and cilta-cel received regulatory approval for the treatment of patients with relapsed or refractory multiple myeloma (MM) after ≥4 prior lines of therapy, and almost all eligible patients in the US and Europe have previously received at least one autologous hematopoietic cell transplant (autoHCT). Even for those who received upfront autoHCT, salvage transplant (either second autoHCT or allogeneic HCT) for patients with relapsed MM was shown to be effective and feasible. Therefore, comparing CAR-T cell therapy with salvage transplant could facilitate future selection of patients with relapsed MM, as eligibility for transplant (especially allogeneic HCT) differs significantly from that of CAR-T.

The role of donor CMV serostatus in the setting of non T-cell depleted haplo-HSCT with post-transplant cyclophosphamide (PT-Cy) has not been specifically addressed so far. Here we analyzed the impact of the donor CMV serological status on the outcome of 983 CMV seropositive (CMV+), acute leukemia patients receiving a first, non T-cell depleted haplo-HSCT registered in the EBMT database. The 1-year NRM was 21.3% (95% CI: 18.4–24.8) and 18.8% (95% CI: 13.8–25.5) in the CMV D+/R+ and D−/R+ pairs, respectively (p= 0.40). Similarly, 1-year OS was 55.1% (95% CI: 50.1–58.0) and 55.7% (95% CI: 48.0–62.8) in the same groups (p= 0.50). The other main outcomes were comparable. No difference in NRM nor OS was observed after stratification for the intensity of conditioning and multivariate anaysis confirmed the lack of significant association with NRM or OS. In conclusion, the choice of a CMV-seronegative donor did not impair early survival of CMV-seropositive patients with acute leukemia after a first, non T-cell depleted haploidentical HSCT and PT-Cy among this series of 983 consecutive patients. Future research may focus on the assessment of the hierarchy of all the donor variables.

Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Late-onset noninfectious pulmonary complications (LONIPCs) after allogeneic hematopoietic cell transplantation (HCT) contribute to posttransplant mortality, morbidity, and decreased quality of life. The effect of newer HCT approaches including reduced intensity and umbilical cord on the incidence and outcome of LONIPC has not been studied. We hereby present a study evaluating the incidence, risk factors, and outcomes of LONIPC in a recent cohort of allogeneic HCT recipients.

Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet α-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B12 as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at www.clinicaltrials.gov as NCT00069680 and NCT00369421.

Introduction:Total body irradiation (TBI) continues to be an important part of the conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in acute lymphoblastic leukemia (ALL). Previous dose escalation studies showed that higher than 12-Gray (Gy) was toxic and did not provide any apparent survival benefit - at least in patients (pts) transplanted in first complete remission (CR1) - thus establishing 12-Gy as the standard TBI dosage. Whether 8-Gy instead of 12-Gy TBI is sufficient in ALL CR1, as has been prospectively demonstrated for AML CR1 (Lancet Oncol 2012; 13: 1035-1044), has not yet been studied.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard of care for adults with high-risk acute lymphoblastic leukemia (ALL) in first or subsequent complete remission (CR). Myeloablative total body irradiation (TBI) combined with cyclophosphamide (Cy) is the most frequently used conditioning regimen. In order to reduce toxicity Cy may be replaced by fludarabine (Flu). The goal of this registry-based, retrospective study was to compare outcomes of allo-HCT following TBI/Cy vs. TBI/Flu conditioning.

Background:Outcomes of Haploidentical transplantation (HaploSCT) in adult patients (pts) with acute relapsed/refractory lymphoblastic leukemia (Rel/Ref ALL) are comparable to unrelated donor transplants. We have recently reported that results of HaploSCT for ALL in remission are not significantly different from those receiving transplants from matched sibling donors (MSD). However, results may differ in ALL pts with active disease.

Therapeutic plasma exchange (TPE) seems to be an effective approach for clearing toxins, immune-mediated antigens, and other particles from the circulation. The aim of this study was to analyze the positive effects of TPE on clinical and biochemical parameters of liver failure.

The aims of this study were to determine the presence of trefoil factor family-3 (TFF3) expression in biliary epithelial cells (BECs) of chronic graft-versus-host disease (cGVHD) of the liver after allogeneic hematopoietic cell transplantation, to compare such expression in chronic liver diseases (CLD) with/without predominantly biliary disease, and to assess the effect of bile duct injury on the degree of TFF3 expression in BECs of cGVHD.

Despite published reports regarding the association of elevated circulating CD44 and CD54 levels with unfavorable outcome in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), little is known about therapy-related changes in either adhesion molecule. In an attempt to evaluate the effect of interferon-α (IFNα), the authors measured serum CD44 (sCD44) and sCD54 in 22 low grade NHL and 14 CLL patients. Twenty-six patients fulfilling the criteria for therapy received daily doses of 3 ×10⁶ IU IFNα-2a. Ten patients not requiring therapy also were observed for the same period. Fasting sera were collected at baseline and in 4 monthly intervals from all patients including the IFNα-treated (Group 1) and the untreated group (Group 2). Higher baseline sCD44 values were observed in Group 1 as compared with the Group 2 patients (P = 0.057). Within Group 1, patients were further divided between those who responded to IFNα, referred to as responders, and those who did not respond to IFNα, known as nonresponders. Responders showed a gradual decrease in sCD44 starting at the 4th month until the 12th month (P = 0.003, P = 0.002, and P = 0.01). Neither a difference in baseline nor an IFNα effect on the sCD54 levels could be shown. Soluble CD44 levels between responders and nonresponders were not different at the baseline but were significantly lower in responders, starting at month 4 and continuing throughout the therapy period (P = 0.04, P = 0.017, and P = 0.043). This decrease did not accompany a leukocyte or lactate dehydrogenase decrease and was not correlated with an early disappearance of the clinical findings. Similarly, after treatment, the sCD44 values of Group 1 were lower than the Group 2 levels at months 4 and 8 (P = 0.007 and P = 0.05, respectively). Soluble CD44, but not sCD54, can be used for monitoring therapy in patients with low grade NHL and CLL who have received IFNα, and for deciding whether further IFN therapy is necessary for those patients who have not responded to IFNα over a previous 12-month period. Cancer 2000;89:1474–81. © 2000 American Cancer Society.

Unmodified allogeneic peripheral blood stem cell transplantation (alloPBSCT) was performed in 20 consecutive acute non-lymphoblastic leukemia (ANLL) patients from their HLA-identical siblings. There were 11 males and 9 females. Median age was 34 years (range 17–43). Donors were primed with 2·5–15 μg/kg/day s.c. granulocyte-colony stimulating factor (G-CSF, Neupogen, Roche). Conditioning regimen was Bu (16 mg/kg)+Cy (120 mg/kg) in 19 patients and high dose Ara-C (3 gr/m² twice daily for 3 days) for one patient who relapsed after bone marrow transplantation. Eighteen patients were in CR1. CsA+short-term MTX (n=19) or CsA alone (n=1) were used for graft versus host disease (GVHD) prophylaxis. The median number of apheresis procedures for each patient was 2 (2–4). A median of 6·5 (3·2–38·2)×10⁸/kg MNC or 9·4 (2·2–12·4)×10⁶/kg CD34+cells were given. Median days to reach granulocyte of >0·5×10⁹/l and platelet of >50×10⁹/l were 12 (10–14) and 15 (11–35) respectively. Day 100 transplant-related mortality was 20 per cent (4/20). Grade 2 to 4 AGVHD was seen in 8 out of 17 (47%) evaluable patients. Severe AGVHD occurred in 3 out of 17 (18%). Clinical CGVHD of all grades developed in 12 out of 17 (70%) evaluable patients. The mean disease-free survival and overall survival were 17 (range: 8–33 months) and 18 months (range: 10–34 months), respectively. In conclusion, alloPBSCT in ANLL is associated with a faster engraftment, no greater incidence of AGVHD, but increased risk of CGVHD. Copyright © 1998 John Wiley & Sons, Ltd.

Abstract: Our two patients undergoing allogeneic bone marrow transplantation (AlloBMT) had both Hepatitis B virus (HBV) and graft-versus-host disease (GVHD). In the first patient,, liver enzymes elevated three months after AlloBMT, and GVHD was diagnosed. Two weeks after the diagnosis of GVHD, HBsAg appeared in his serum. At that time, liver biopsy was not able to discriminate two disorders, but his sequential liver biopsies disclosed GVHD. Despite the patient was treated with cyclosporin A (CsA), he died for chronic GVHD. In contrast to the first patient, the second patient had HBsAg prior to GVHD. His liver enzymes deterioration was detected in the first month after AlloBMT, and reached the highest level in the third month while withdrawing CsA. In the fifth month he developed scleradermatous skin changes, and skin biopsy revealed chronic GVHD, whereas concurrent liver biopsy revealed chronic active hepatitis. This observation showed that immunosuppressive conditions such as GVHD or its prophylaxis may affect the appearance of liver pathology caused by HBV, which depends on the time of GVHD development, and the duration and depth of GVHD prophylaxis.

Various regimens have been explored in the treatment of acute nonlymphoblastic leukaemia (AML), but so far none has been shown to be superior. Here we report on a comparison of three widely used protocols defined by Berman (Group 1), MRC AML 10 (Group 2), and Arlin (Group 3). Group 1 includes cytosine arabinoside (Ara-C) (100 mg/m2/d, days 1–7) and idarubicin (Ida) (12 mg/m2/d, days 1–3) for induction, and Ara-C (200 mg/m2/d, days 1–6) and Ida (15 mg/m2/d, day 1) twice for consolidation. Group 2 includes Ara-C (200 mg/m2/d, days 1–10), daunorubicin (Dnc) (50 mg/m2/d, days 1, 3, 5) and etoposide (VP16) (100 mg/m2/d, days 1–5) for induction. The first consolidation therapy consisted of the same schedule except for Ara-C given on days 1–8. The second consolidation regimen consisted of Ara-C (200 mg/m2/d, days 1–8), VP16 (100 mg/m2/d, days 1–5) and amsacrine (100 mg/m2/d, days 1–5). Mitoxantrone (Mitox) (10 mg/m2/d, days 1–5) and Ara-C (200 mg/m2/d, days 1–3) were given as the third consolidation therapy. Group 3 was identical to Group 1 except for Ida being replaced with Mitox. During the study period 99 patients were enrolled and 34 were allocated randomly to Group 1, 36 to Group 2, and 29 to Group 3. Except for age distribution all patients’ characteristics were similar between the groups. As there were more elderly patients in Group 1, time to complete remission (CR) was longer in this group as they needed more second induction. Induction deaths were 9.7%, 12.9% and 14.8% in Groups 1, 2 and 3, respectively. Patients in Group 2 received a higher amount of Ara-C compared with the other groups (P<0.001). After a median follow-up period of 45 months (1–67 for survivors) an advantage in Group 1 was observed. Relapse-free survival (RFS) was better in Group 1 (P=0.014) at 3 years. Fourteen of the patients were transplanted (11 allografts, 3 autografts). When patients with transplants were excluded, overall survival was longer in Group 1 both at 3 years and 5 years (P=0.05). In conclusion, despite patient advanced age and lower dose of Ara-C, the idarubicin-containing treatment was superior to the other regimens.

The oral cavity is one of the most common sites impacted by hematopoietic stem cell transplantation (HSCT) with acute complications including mucositis, bleeding, salivary gland dysfunction, infection, and taste alteration. These complications may result in significant morbidity and can negatively impact outcomes such as length of stay and overall costs. As such, oral care during HSCT for prevention and management of oral toxicities is a standard component of transplant protocols at all centers. The objective of this study was to evaluate the current oral care practices for patients during HSCT at different transplant centers within the Eastern Mediterranean region.