Zaid Al-Kadhimi

High Incidence of Severe Acute Graft-Versus-Host Disease with Tacrolimus and Mycophenolate Mofetil in a Large Cohort of Related and Unrelated Allogeneic Transplantation Patients

Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patients age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.

Large pericardial effusion as a complication in adults undergoing SCT

Large pericardial effusion (LPE) leading to cardiac tamponade is a rare complication described in patients undergoing SCT. This complication is considered to be a manifestation of chronic GVHD; however its pathophysiology is poorly understood. Currently, there are no published data systematically describing the incidence, clinical characteristics and outcomes of LPEs in adult stem cell transplant recipients. We retrospectively evaluated 858 adult patients (512 autologous, 148 related and 198 unrelated donor) who underwent hematopoietic stem cell and BM transplants at our institution from 2005 to 2008 for the development of post transplant LPE. Seven patients (0.8%) were found to have LPEs and all these patients had undergone unrelated allografts. The median day of diagnosis post transplant was 229 (range 42–525). None of these patients had active manifestations of GVHD other than serositis at the time of LPE detection. Pericardial window (PW) was successfully placed in all patients who developed cardiac tamponade and most patients with LPE were effectively treated by increasing immunosuppression. We conclude that LPE is a rare late complication after allogeneic transplant in adults and in our study developed only after unrelated transplant. PW can be safely performed in these patients and LPEs can be successfully treated with intensification of systemic immunosupression.

Incidence, Risk Factors, and Outcome of Cytomegalovirus Viremia and Gastroenteritis in Patients with Gastrointestinal Graft-versus-Host Disease

Gastrointestinal (GI) graft-versus-host disease (GVHD) is one of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia at a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P < .001). The incidence of CMV viremia with relation to donor (D) and recipient (R) CMV serostatus subgroups was as follows: D+/R+, 73%; D-/R+, 67%; D+/R-, 19%; and D-/R-, 0. A total of 31 patients were diagnosed with a biopsy-proven CMV gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D-/R+, 31%; D+/R-, 12%; and D-/R-, 0. Median follow-up time for the 252 patients was 35.4 (95% CI 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P < .001) and development of CMV gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis.

Long-term follow up of patients proceeding to transplant using plerixafor mobilized stem cells and incidence of secondary myelodysplastic syndrome/AML.

We report the long-term follow up of 49 patients (pts) enrolled on plerixafor compassionate use protocol. Thirty-seven pts (76%) had failed one previous mobilization attempt, while 12 (24%) had failed two or more previous attempts. Using the combination of plerixafor and granulocyte colony-stimulating factor, we collected⩾2.5 × 106 CD34+cells/kg in 33 pts (67%). Forty-three of the 49 pts proceeded to an auto-SCT (ASCT). The median days to WBC and platelet engraftment were 11 (range, 9–13 days) and 16 (range, 11–77 days) days post ASCT, respectively. The median WBC count, Hb and platelet counts 1 year after ASCT were 4.7 × 109/L, 12.2 g/dL and 109 × 109/L, respectively. With median follow up of 42 months (range <1–54 months), 21 pts had evidence of disease progression. Five pts developed myelodysplastic syndrome (MDS)/AML at median of 29 months post ASCT. The cumulative incidence of MDS/AML at 42 months was 17% (95% confidence interval, 6 to 32%). Development of secondary MDS/AML in pts proceeding to ASCT after plerixafor mobilization needs to be studied further in a larger cohort.

PD-1 and CTLA-4 up regulation on donor T cells is insufficient to prevent GvHD in allo-HSCT recipients.

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients.

Successful hematopoietic stem cell collection in patients who fail initial plerixafor mobilization for autologous stem cell transplant.

We report our experience of collecting stem cells in patients who failed to mobilize sufficient hematopoietic stem cell (HSC) using plerixafor (P) in the initial mobilization attempt. Twenty four patients were identified who failed a first mobilization attempt using P. Of these, 22 patients received granulocyte colony stimulating factor (G‐CSF) and two patients received cyclophosphamide (CY) + G‐CSF in combination with P for the initial attempt. The agents used for second collection attempt were granulocyte macrophage colony stimulating factor (GM‐CSF) + G‐CSF (19 patients), G‐CSF + P (three patients), CY + G‐CSF (one patient), and bone marrow harvest (one patient). A median of 0.6 × 106 CD34+ cells/kg (range 0–1.97) were collected in the initial attempt. A second collection was attempted at a median of 22 days (range 15–127) after the first failed mobilization. The median CD34+ cell dose collected with the second attempt was 1.1 × 106 CD34+ cells/kg (range 0–7.2). A third collection was attempted in six patients at median of 51 days (range 34–163) after the first failed mobilization. These patients collected a median of 1.1 × 106 CD34+ cells/kg (range 0–6.5). Total of 16 patients (67%) collected sufficient cells to undergo autologous stem cell transplant and eight patients (33%) were able to collect ≥2 × 106 CD34+ cells/kg in a single subsequent attempt. Our experience suggests that a majority of patients who fail primary mobilization despite use of P can collect sufficient HSC with a subsequent attempt using combination of G‐CSF with either P or GM‐CSF. J. Clin. Apheresis 29:293–298 2014.

Peritransplantation Red Blood Cell Transfusion Is Associated with Increased Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day -7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P = .01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P = .02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P = .005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P = .054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.

A phase II study of tacrolimus and thymoglobulin as graft-versus-host-disease prophylaxis in related donor allogeneic hematopoietic cell transplantation

Ayalew Tefferi , Sravanthi Lavu , Mythri Mudireddy , Terra L. Lasho, Christy M. Finke, Naseema Gangat , Animesh Pardanani, Curtis A. Hanson, Carmela Mannarelli, Paola Guglielmelli, Alessandro M. Vannucchi Division of Hematology, Mayo Clinic, Rochester, Minnesota Division of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy

Comparable outcomes following two or three cycles of high-dose chemotherapy and autologous stem cell transplantation for patients with relapsed/refractory germ cell tumors

Germ cell tumors are among the most curable of solid tumors, with long-term durable remissions seen in 480% of good-risk patients and 50–60% of poor-risk patients. However, in 20–30% of patients, the tumor persists or recurs after initial treatment and salvage therapies are required. High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (HDC–HSCT) is a potentially curative approach for this previously treated population, with reported long-term post-transplant survival as high as 70%. Questions remain regarding the optimal regimen of HDC and the timing of its use. We reviewed our institutional experience with two different sequential HDC regimens for previously treated germ cell tumors to evaluate and compare the outcomes with this salvage approach. All patients with previously treated germ cell tumors who received HDC–HSCT at Emory University Hospital between 2002 and 2014 were identified from the transplant database. Patients were either diagnosed and treated at our institution with standard induction chemotherapy with subsequent diagnosis of relapsed/ refractory disease or specifically referred at time of progression for HDC–HSCT. Baseline data on the initial presentation and treatment of germ cell cancer, the transplant maneuver and post-transplant outcomes were extracted from the institutional transplant database and the individual medical record of each patient. The Emory University Institutional Review Board approved this retrospective analysis and all patients completed the informed consent for inclusion in the database at the time of their transplant. Transplant-eligible patients were consented and scheduled to receive two or three planned cycles of HDC (2HDC and 3HDC) with autologous stem cell support. Each cycle of HDC consisted of carboplatin and etoposide, and was administered according to the previously published regimens. The 2HDC regimen consisted of stem cell mobilization consisting of growth factors ± chemotherapy with two cycles of high-dose carboplatin (700 mg/m, days 1–3) and etoposide (750 mg/m, days 1–3) planned to be given at one-month intervals followed by autologous PBSC support. The 3HDC regimen consisted of two cycles of paclitaxel (200 mg/m, day 1) and ifosfamide (2 g/m/day, days 2–4) given 14 days apart (in conjunction with growth factor mobilization) followed by three cycles of high-dose carboplatin (dosed to an area-under-curve of 24, divided over days 1–3) and etoposide (400 mg/m/day, days 1–3), each with autologous PBSC support planned to be given at 21-day intervals. The International Germ Cell Cancer Collaborative Group (IGCCCG) classification at diagnosis and the International Prognostic Factors Study Group (IPFSG) risk score for salvage therapy were calculated according to the published algorithms. The probability of overall survival (OS) was estimated with the use of the Kaplan–Meier method. OS was defined as the time from the date of first HSCT to the date of death or last contact. The SPSS statistical package (version 22.0; SPSS, Chicago, IL, USA) was used for all data analyses. Between January 2002 and December 2014, 27 patients received HDC–HSCT for germ cell tumors. A single patient who achieved a durable remission following the treatment of recurrent central nervous system (CNS) germinoma with a thiotepa-based HDC–HSCT regimen was excluded from the analysis. Patient and disease characteristics of the 26 patients with germ cell cancer who underwent autologous stem cell transplantation are detailed in Table 1. Twenty-three were males and three were females. The median age at diagnosis was 30 years (range, 20–61). The majority had nonseminoma/mixed histology (n= 21, 81%), whereas three had seminoma (12%) and two had ovarian germ cell tumors (8%). The primary sites of disease were gonadal (n= 20), retroperitoneal (n= 2), or mediastinal (n= 4). A total of 58% of patients had metastatic disease (pulmonary only, n= 10; non-pulmonary visceral, n= 5). All patients had been previously treated, with 35% receiving one prior line of treatment, 54% receiving two lines and 12% receiving ⩾ 3 lines of chemotherapy. Six patients (23%) had cisplatin-refractory disease (defined as progression within 4 weeks of cisplatin therapy). The IPFSG score shows that a higher proportion of patients with lowor very low-risk disease received the 3HDC regimen when compared with the 2HDC regimen. As shown in Table 1, the patients receiving 2HDC or 3HDC have no significant difference in any of the factors except the year of transplant. Therefore, the two groups are comparable in terms of demographics and baseline characteristics. The median follow-up for survivors was 4.45 years (range, 5 months–13 years). Fourteen of 15 patients (93%) in which the 3HDC regimen was planned completed all three transplants, whereas only 8 of 11 (73%) patients on the 2HDC regimen completed the two planned transplants. Reasons for not completing the planned therapy included progressive disease (n= 1, 2HDC; n= 1, 3HDC), regimen-related toxicity (n= 1, 2HDC), and physician/patient preference (n= 1, 2HDC). Five patients had surgical resection of residual tumor following the transplant, three of whom had pathologic evidence of viable disease. The OS at 3 years for the whole group was 51%, with the OS according to chemotherapy regimen shown in Figure 1a (2HDC: n= 11, OS 55%; 3HDC: n= 15, 46%; P-value = 0.9217) and OS according to IPFSG score shown in Figure 1b (very low/low/intermediate: n= 15, OS 55%; high/very high: n= 11, OS 45%, P-value = 0.4169). The OS at 3 years for the four patients with primary mediastinal nonseminomatous disease (all received 3HDC) was 75%. The OS at 3 years for the six patients (n= 3, 2HDC; n= 3, 3HDC) with cisplatin-refractory disease was 83%. There were no deaths attributed to the toxicity from HDC and autologous HSCT. There were 10 deaths in total, all due to the progressive disease. From Table 1, the two groups (2HDC vs 3HDC) differed significantly only in the year of transplant, with a marginal difference in the IPFSG score at transplant. As the two groups of patients (2HDC vs 3HDC) were Bone Marrow Transplantation (2017) 52, 132–134

Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for GvHD prevention

Chronic GvHD (cGvHD) is the leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic stem cell transplant (AHSCT). We analyzed the late effects of a phase II trial testing the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymoglobulin Thymo) in combination with tacrolimus and sirolimus (TTS) in 47 patients (pts) for the prevention of acute and chronic GvHD after unrelated AHSCT. The median follow-up was 45.2 months. The cumulative incidence of NIH severe cGvHD at 48 months was 6.4% with no new occurrences past 6 months for the entire follow-up period. The overall cumulative incidence of cGvHD was 44.7%. Out of 20 pts who are alive and disease-free at the last follow-up, only 4 pts continue to need systemic immune suppression. We observed low late NRM with only 3 transplant-related deaths after 6 months post transplant. At 4 years of follow-up, the overall cumulative incidence of NRM and disease relapse was 27.7% and 30.0%, respectively. PFS and overall survival (OS) at 4 years were 42 and 47%. At long term follow-up, TTS was associated with low incidence of severe cGvHD and late NRM.