GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes.

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (⩾18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Secondary solid cancer screening following hematopoietic cell transplantation.

Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well-documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients.

Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience.

Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.

The number of infused CD34+ cells does not influence the incidence of GVHD or the outcome of allogeneic PBSC transplantation, using reduced-intensity conditioning and antithymocyte globulin.

The influence of graft composition on the outcome of reduced-intensity (RIC) allogeneic PBSC transplantation (allo-PBSC) remains controversial. In this study, we analyzed the impact of CD34+ cell dose on the incidence of GVHD, and on the outcome after allo-PBSC, in 103 patients with hematological malignancies, using a uniform RIC regimen. The following variables were included in statistical analysis: (1) number of C34+ cells, (2) high-risk vs low-risk disease status, (3) matched related vs matched unrelated donor, (4) female donor to male recipient vs any other combination, (5) age of recipient (above vs below the median). Univariate and multivariate analysis did not reveal any association between CD34+ cell dose and acute grade-2 to grade-4, cGVHD, non-relapse mortality (NRM), relapse rate (RR) and OS. High-risk disease status was the only variable independently associated with increased NRM (P=0.001), increased RR (P=0.012) and decreased OS (P<0.001). The same results were obtained when analysis was restricted to a subgroup of 55 patients with myeloid neoplasms. The influence of graft composition on the outcome of RIC allo-PBSC should be further investigated via well-controlled randomized prospective studies.

Alefacept treatment for refractory chronic extensive GVHD.

Alefacept (Amevive) is an immunosuppressive dimeric fusion protein that is used for psoriasis control. We recently showed its effect in acute steroid-resistant/dependent GVHD. In this study, we describe the effect of alefacept treatment on chronic extensive GVHD (cGVHD). Twelve patients were included in this study; of these 8 (9 of 13 episodes) showed response. The median time to initial response was 2.25 weeks and the response was marked (n=3), moderate (n=2) or minimal (n=4). In two responding patients, the response was only temporary. Complications that appeared during treatment included infection, pericarditis and squamous cell carcinoma of the lip. All these events may be related to other drugs given simultaneously. With a 30-month median follow-up, 6 of 12 patients are alive, with all but one with stable or improved cGVHD. Six patients died because of GVHD progression, whereas none of the patients experienced relapse of the disease for which the transplantation was done. As reported earlier in psoriatic patients treated with alefacept, we found a consistent increase in the percentage of naive T cells as a consequence of treatment. In conclusion, alefacept is effective for the treatment of cGVHD, and dose and time intervals of treatment should be explored further.

Time to engraftment following allogeneic stem cell transplantation is significantly longer in patients with myelodysplastic syndrome than with acute myeloid leukemia.

Patients with myelodysplastic syndrome (MDS) commonly present with pancytopenia, suggesting that the marrow stroma fails to support the growth of both malignant and normal stem cells. We therefore retrospectively analyzed the duration to engraftment of neutrophils (> or =0.5 x 10(9)/l and > or =1.0 x 10(9)/l) and platelets (> or =20 and > or =50 x 10(9)/l) in 37 MDS patients and 42 patients suffering from primary AML, following allogeneic SCT. A significantly shorter time to engraftment was documented in AML as compared to MDS patients in all four parameters. These results held true even when we subgrouped the patients according to gender, age (50 years being the cutoff age between young and elderly patients), patient-donor relationship, donor match and intensity of conditioning. To the best of our knowledge, this is the first time that such a comparison has been made. We suggest that the longer duration of post transplant pancytopenia that is frequently observed in MDS patients may also influence post transplant outcome.

Peliosis hepatis following treatment with androgen-steroids in patients with bone marrow failure syndromes.

Androgens widely used in the treatment of bone marrow failure syndromes can in rare cases cause hepatic peliosis, a pathological entity characterized by multiple blood-filled cavities in the liver parenchyma. Bone marrow failure syndromes per se are associated with a low coagulation status, which is further magnified by bone marrow transplantation for aplastic anaemia due to deep thrombocytopenia. Both these conditions can cause bleeding; their combination is especially dangerous. We describe two cases of aplastic anaemia due to paroxysmal nocturnal hemoglobinuria and Fanconi syndrome, in which patients developed peliosis hepatis after prolonged treatment with androgens. One patient developed severe subcapsular bleeding, successfully treated with catheterization of the right hepatic artery and embolization of the bleeding site. The second patient bridged over deep post-transplant aplasia with high frequency platelet transfusions, and demonstrated an uncomplicated post-BMT course. We suggest avoiding or interrupting treatment with androgens in patients preparing for BMT.

Allogeneic stem cell transplantation from matched related and unrelated donors in thalassemia major patients using a reduced toxicity fludarabine-based regimen.

The only radical cure for thalassemia major patients today is the replacement of the defective hematopoietic system by allogeneic stem cell transplantation (allo-SCT). The major obstacles for the application of allo-SCT even from matched family members have been the transplant-related morbidity and mortality and graft failure that is usually associated with the recurrence of the thalassemia hematopoiesis. The outcome of allo-SCT from HLA-identical family donors is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload. In this study we report our experience of allo-SCT from matched related and unrelated donors, using a reduced toxicity conditioning consisting of fludarabine, busulfan or more recently busulfex and antithymocyte globulin, in a cohort of 20 patients with thalassemia major. The regimen-related toxicity was minimal, while the incidence of acute grade II-IV and chronic GVHD was 25 and 25%, respectively. With a median follow-up period of 39 months (range: 5-112 months) the overall survival was 100%, while thalassemia-free survival was 80%. Although the results of our study look promising, larger cohorts of patients and prospective clinical trials are required to confirm the benefits of our approach as a possible better alternative to the existing protocols.

A patient with progressive multiple myeloma treated successfully with arsenic trioxide after allogeneic bone marrow transplantation.

Multiple myeloma (MM) is an incurable progressive disease. Many therapeutic options are available to delay progression, including autologous and allogeneic bone marrow transplantation. At advanced stages, MM is often refractory to treatment. We report a heavily pretreated patient with graft-versus-host disease after bone marrow transplantations, treated at a terminal stage with a modified protocol for arsenic trioxide (ATO). This patient with poor clinical status tolerated the treatment very well. He had a remarkable clinical response and achieved complete remission. The mechanisms of ATO are presented and the potential role of ATO for MM is discussed.

Safety and efficacy of donor lymphocyte infusions following mismatched stem cell transplantation.

The use of a mismatched allograft necessitates T cell depletion for prevention of uncontrolled graft-versus-host disease (GVHD), thus impairing a graft-versus-leukemia effect. Data on donor lymphocyte infusion (DLI) after mismatched stem cell transplantation are lacking. Our experience with 28 patients (treated with 59 mismatched DLIs; range, 1-7) is described. The procedure was prophylactic in 6 patients (9 DLIs) and therapeutic in 22 (50 DLIs). DLI dose ranged from 10(2) to 1.5 x 10(9) T cells/kg. In the 6 patients receiving prophylactic DLI, complete remission was maintained in 5; however, 2 died from GVHD. Clinical response to therapeutic DLI was seen in 6 of 22 (27.3%) patients; a greater tumor burden produced a lower response. GVHD appeared in 13 of 28 patients. Surprisingly, a greater HLA mismatch was associated with a lower risk of GVHD, with 3 of 19 DLIs in 3/6 matching and 16 of 29 DLIs in 5/6 matching with similar follow-up. Nevertheless, no correlation between efficacy and HLA mismatching was noted. Death was frequent and usually related to the basic disease rather than to DLI complications. We conclude that mismatched DLI is feasible and may be effective, especially if given soon after transplantation. Future developments using cell therapy with selective or targeted anticancer activity are warranted, with special attention to prophylactic treatment of T cell depleted mismatched allografts recipients.

Treatment of post-hematopoietic stem cell transplantation hemorrhagic cystitis with intravesicular sodium hyaluronate.

Hemorrhagic cystitis (HC) is a well-known complication of HSCT. Its overall incidence has been reported to vary from 7-68%. The spectrum of clinical presentation varies from asymptomatic microhematuria to life-threatening bleeding. Sodium hyaluronate is a glycosaminoglycan present on the bladder mucosa, which serves as an important protective substance against uroepithelial damage. Preparations of this component have been shown to be effective in the treatment of interstitial cystitis. We report our experience in the treatment of post-transplant HC with intravesical instillation of sodium hyaluronate. Five out of the seven patients included in this study achieved complete response, while one patient had only partial response. Sodium hyaluronate administration was not associated with any local or systemic adverse effects. We consider that the results of our study are promising and the efficacy of sodium hyaluronate in the treatment of post-transplant HC should be tested in larger cohorts of patients.

Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors.

Reduced intensity conditioning has been suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications, but it seems particularly attractive for patients with Fanconi anemia due to their increased sensitivity to chemoradiotherapy. Between November 1996 and September 2003, 7 patients (1 male and 6 female; age range, 3-31 years; median age, 9.5) were conditioned with a fludarabine-based protocol for stem cell transplantation without radiation. In vivo T-cell depletion was accomplished with anti-thymocytic globulin or Campath-1H (alemtuzumab). Graft-versus-host disease prophylaxis consisted of low-dose cyclosporine alone. Eight transplantations were carried out for 7 patients using bone marrow, peripheral blood, and/or cord blood as sources of stem cells. All patients received transplants from HLA-A, -B, -C, and -DR matched donors, 5 from family members and 2 from matched unrelated donors. One patient did not engraft her first matched unrelated donor and underwent a second transplantation from another matched unrelated donor, after which she engrafted well. All 7 patients are alive and well, fully reconstituted with donor cells, and with 100% performance status. In conclusion, fludarabine-based preparative protocols are well tolerated, facilitate rapid engraftment with minimal toxicity, and should be considered an essential component of choice for patients with Fanconi anemia.

A prospective, double-blind phase II study evaluating the safety and efficacy of a topical histamine gel for the prophylaxis of oral mucositis in patients post hematopoietic stem cell transplantation.

The aim of this study was to evaluate the safety, tolerability and efficacy of a topical gel containing histamine dihydrochloride (HDC) versus a placebo gel in preventing oral mucositis in hematopoietic stem cell transplantation (HSCT) patients. A total of 45 patients post-HSCT were enrolled in a prospective longitudinal, placebo-controlled, double-blind study. Patients were evaluated twice weekly for oral mucositis (OMAS, NCI score), oral pain (VAS), oral function and salivary flow rate. Compliance was assessed using a patient diary. Oral mucositis developed in 85% of the HDC group and 63% of the placebo group. The mean maximal intensity for NCI score was 1.45+/-1 in the HDC group and 1.21+/-1.27 in the placebo group (P=0.37). The mean duration of oral mucositis was 4.7+/-3.6 and 2.33+/-2.23 days in the HDC and placebo groups, respectively (P=0.06). The same trends were measured with OMAS. Visual analogue scale for oral pain and oral function was not significantly different between the two groups. Histamine dihydrochloride was found to be safe. In the search for topical agents for the prevention of mucositis, we found that HDC neither improves nor worsens oral mucositis in HSCT patients. The balance between the pro- and anti-inflammatory effects of HDC should be investigated further in order to acquire a clinically effective topical medication based on its anti-inflammatory properties.

Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report.

We evaluated the effect of alefacept (Amevive), a novel dimeric fusion protein, in steroid resistant/dependent acute graft-versus-host-disease (aGVHD). Seven patients were treated in eight aGVHD episodes. GVHD grade at treatment initiation and at peak ranged 2-4 (median 2.5) and 2-4 (median 4), respectively. System involvement at GVHD peak included skin (n=7), gastrointestinal tract (n=5) and liver (n=3). All patients responded. However, one patient with skin GVHD and two with gastrointestinal GVHD featuring an early initial response (IR) exacerbated and CR was not achieved. Skin GVHD responded rapidly with a median of 1 day to IR and 7 days to CR. Intestinal response was slower with median 7.5 days to IR. Of the four patients that achieved IR, CR was achieved in only one (40 days to CR). None of the patients had significant hepatic GVHD before treatment so no hepatic effect of alefacept could be determined. No immediate alefacept-related side effects were observed. Late side effects included infections (aspergillus sinusitis, pneumonia, bacteremia, pharyngeal thrush), pancytopenia and hemorrhagic cystitis. Three patients had CMV reactivation while on alefacept. We conclude that alefacept may have a beneficial effect in controlling aGVHD. Further investigations in larger cohorts of patients and controlled studies are warranted.

Nonmyeloablative stem cell transplantation using lymphoablative rather than myeloablative conditioning in the prefludarabine era by ATG and limiting doses of cyclophosphamide.

The feasibility of using lymphoablative rather than myeloablative conditioning for durable engraftment of allogeneic stem cells and subsequent cell therapy with donor lymphocytes was pioneered in the prefludarabine era in patients with resistant lymphoma and metastatic solid tumors. Between July 1995 and August 1996, 15 patients, five males and 10 females, median age 50 (range 20-57) years, were enrolled in a protocol that consisted of different doses of cyclophosphamide (Cy), 50 mg/kg/day for 1, 2, 3 or 4 consecutive days in parallel with a fixed dose of rabbit antithymocyte globulin (ATG) (Fresenius) 10 mg/kg/day for 4 consecutive days. All patients, except one treated with a single dose of Cy, achieved full tri-lineage engraftment and no late graft failure was observed. Only three patients suffered from grade III-IV graft-versus-host disease (GVHD). Three patients out of the 15 survived long term (follow-up >93 to >96 months). We concluded that lymphoablative conditioning with ATG and intermediate-to-high-dose Cy is well tolerated and can result in durable engraftment with acceptable GVHD in heavily pretreated patients with advanced malignancies. Hence, induction of tolerance to donor alloantigens by lymphoablative conditioning while avoiding myeloablative chemotherapy or radiation therapy may serve as a platform for subsequent cell therapy with donor lymphocytes.

Low transplant-related mortality with allogeneic stem cell transplantation in elderly patients.

Historically, age >60 years was considered a contraindication for allogeneic stem cell transplantation (allo-SCT). In recent years, elderly (>60 years) patients have become eligible for allo-SCT due to the application of reduced intensity conditioning (RIC). The present report summarizes our cumulative experience in a cohort of 17 elderly patients (age 60-67, median 62.5 years) with hematological malignancies treated with 18 allo-SCT procedures, mostly nonmyeloablative. In all, 14 patients received fludarabine and busulfan/busulfex regimen, three patients were conditioned with the fludarabine and low-dose TBI and one patient received busulfan alone. All patients displayed tri-lineage engraftment. The time to recovery of absolute neutrophil count >/=0.5 x 10(9)/l was 9-27 days (median 14 days). The time interval to platelet recovery >/=20 x 10(9)/l was 3-96 days (median 11 days). Veno-occlusive disease occurred only in 3/18 procedures and subsided with conventional treatment. Nonfatal transplant-related complications occurred in 6/18 (33.3%) procedures including: renal failure, arrhythmia, CNS bleeding, cystitis, typhlitis and gastrointestinal bleeding. Transplant-related mortality occurred in 6/18 (33.3%) episodes. Of the 17 patients, 12 (12/18 episodes) were discharged. Five of 17 (29%) patients survived (median follow-up 11 m, range 8-53 m). Our data suggest that RIC-allo-SCT may be safely applied in the elderly, suggesting that allogeneic immunotherapy may become an important tool for treatment of hematological malignancies without an age limit.

Tube thoracostomy during allogeneic stem cell transplantation does not carry an increased risk for infections or bleeding.

BACKGROUND: Candidates for stem cell transplantation may occasionally suffer from massive pleural effusions related to their disease and require tube thoracostomy. The additional risk of this procedure during allogeneic transplantation procedure is not known. METHODS: Four high-risk patients transplanted in our institution during a 2-yr period had chest drainage by tube thoracostomy. The characteristics of the fluid, the clinical course, and the outcome were assessed. RESULTS: A total of nine chest drains were inserted (range 1-5). No bleeding complications related to the procedure were noted. None of the patients developed any clinical signs of local infection at the tube insertion site or within the pleural fluid. All cultures taken from the drained fluid or from the insertion wound were negative. CONCLUSIONS: Tube thoracostomy in itself does not seem to pose additional risks in the transplant procedure, despite all patients in this series being considered to be at high-risk for complications.

CO2 laser in oral graft-versus-host disease: a pilot study.

This paper is the first to report the benefits of CO2 laser treatment for pain control in severe oral chronic graft-versus-host disease (GVHD). A CO2 laser device was used during 17 treatment sessions in four patients. The CO2 laser was applied over the mucosal lesions using 1 W for 2-3 s/1 mm(2). This treatment resulted in a consistent and significant decrease in pain, measured using a standard visual analogue scale. These results suggest that the CO2 laser can be used for the alleviation of pain in oral chronic GVHD.

Rhinolalia as a presenting sign of pneumomediastinum complicating post peripheral blood stem cell transplantation bronchiolitis obliterans.

A 26-year-old male with graft vs. host disease (GVHD) presented with rhinolalia (a squeaky voice of nasal quality) as a presenting sign for pneumonasopharynx and pneumomediastinum secondary to bronchiolitis obliterans. The patient underwent HLA-identical related peripheral blood stem cells transplantation 8 months before the diagnosis. Three weeks after transplantation he began to suffer from GVHD Grade III that involved the gut, liver, and skin and later on the lungs. Due to severe obstructive bronchiolitis obliterans the patient developed intensive cough evolving into pneumomediastinum and pneumonasopharynx with rhinolalia. The patient was treated conservatively with complete resolution. Although rare, pneumomediastinum and pneumonasopharynx can be a life-threatening event, and one should be aware of the signs and symptoms on physical examination, which may be as subtle as rhinolalia alone.

A new minimally ablative stem cell transplantation procedure in high-risk patients not eligible for nonmyeloablative allogeneic bone marrow transplantation.

Nonmyeloblative stem cell transplantation (NST, SCT) aims to induce host-versus-graft tolerance for subsequent immunotherapy of underlying disease with alloreactive donor lymphocytes, focusing on well-tolerated conditioning suitable for elderly individuals or for other risk factors. However, there is a subset of high-risk patients who cannot tolerate NST. A new protocol consisting of fludarabine 30 mg/m(2) x 6 days (days -8 to -2), very-low-dose busulfan (2 mg/kg x 2 days, days -6 to -5), without anti thymocyte globulin (ATG), was employed in 11 high-risk patients aged 26-58 years. Graft-versus-host-disease (GVHD) prophylaxis consisted of low-dose and short-course cyclosporine-A (CSA) alone. One patient died during the nadir due to pulmonary complications. Other patients showed rapid three-lineage engraftment, without complete aplasia; 6/10 patients did not require platelet transfusion and 8/10 had full donor chimerism without transient mixed chimerism. Owing to intentional selection of highly poor-risk patients, overall mortality was high and only one patient survived. Acute GVHD (>/=grade I) occurred in 8/10 evaluable patients, 5/8 while off CSA; 5/8 developed grade III-IV acute GVHD. It appears that our modified, minimally ablative stem cell transplantation (MST) may be used for high-risk patients in need of allo-SCT. Furthermore, although the MST conditioning is not myeloablative, it results in myeloablation of the host hematopoietic system, mediated by alloreactive lymphocytes.