Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men.

In this study, we explored dermal dendritic cell (DC) homeostasis in mice and humans both in the steady state and after hematopoietic cell transplantation. We discovered that dermal DCs proliferate in situ in mice and human quiescent dermis. In parabiotic mice with separate organs but shared blood circulation, the majority of dermal DCs failed to be replaced by circulating precursors for >6 mo. In lethally irradiated mice injected with donor congenic bone marrow (BM) cells, a subset of recipient DCs remained in the dermis and proliferated locally throughout life. Consistent with these findings, a large proportion of recipient dermal DCs remained in patients' skin after allogeneic hematopoietic cell transplantation, despite complete donor BM chimerism. Collectively, our results oppose the traditional view that DCs are nondividing terminally differentiated cells maintained by circulating precursors and support the new paradigm that tissue DCs have local proliferative properties that control their homeostasis in the steady state. Given the role of residual host tissue DCs in transplant immune reactions, these results suggest that dermal DC homeostasis may contribute to the development of cutaneous graft-versus-host disease in clinical transplantation.

Non-myeloablative conditioning and allogeneic transplantation for multiple myeloma.

In multiple myeloma (MM), allogeneic stem cell transplantation (alloHCT) carries a lower relapse risk than autologous transplantation but a greater transplant-related mortality. Nonmyeloablative conditioning for allogeneic transplantation (NST) reduces transplant-related toxicity. Results are encouraging when used during first remission in low-risk patients, but less-so in relapsed or refractory disease. This is a single-center retrospective analysis of 20 previously treated MM patients who underwent NST from matched-related or matched-unrelated donors from 2000-2006. Median age was 52.7 years (37.2-68.0). Twenty-five percent had advanced or high-risk disease. Eleven still had active disease prior to NST. Conditioning was total body irradiation 200 cGy on a single fraction on day -5, followed by antithymocyte globulin (ATG) 1.5 mg/kg/day and fludarabine 30 mg/m(2)/day on days -4 to -2. All received immunosuppression, most commonly with oral mycofenylate mofetil and cyclosporine beginning on day -5. At day 100, 50% had achieved complete remission. Transplant-related mortality was 25%. Median overall survival (OS) was 21.2 months (0.6-90+) and progression-free survival (PFS) 6.6 months (0.6-90+). Both OS and PFS were 24% at 3 years. OS was significantly greater for patients with age <52 years (median 27 months vs. 7.9 months, P = 0.031), and there was a trend toward greater OS for those with beta2 microglobulin <2.5 mg/l (median 27 months vs. 7.7 months, P = 0.08). Donor characteristics and Ig type had no significant effect on survival. These data suggest a benefit of NST in relapsed/refractory MM. Randomized trials must be performed to confirm and further qualify this benefit.

Combined bone marrow and peripheral blood progenitor cell autografts for patients with poor mobilization.

BACKGROUND AIMS: Peripheral blood progenitor cell (PBPC) autografts with low CD34(+) cell content provide inadequate platelet (Plt) and red blood cell (RBC) reconstitution. Repeat collection and bone marrow (BM) harvesting are used in this situation. Minimum cell contents for BM-PBPC combined grafts are undefined. METHODS: A retrospective analysis of 19 autologous stem cell transplants (ASCT) with combined BM-PBPC for poor initial PBPC collection was carried out. Mobilization was with filgrastim (10 microg/kg/day) alone for 5 days or after chemotherapy. BM was harvested if PBPC collections were CD34+<2.5 x 10(6)/kg. RESULTS: The median age was 55 years (range 19-74). The diagnoses were multiple myeloma (7), non-Hodgkin's lymphoma (7), Hodgkin's disease (4) and acute myeloid leukemia (1). The median cell content (CD34+/kg x 10(6)) was 1.1 (0.3-2.7) for BM, 1.2 (0.04-2.8) for PBPC and 2.2 (1.4-4.9) combined. Eight grafts contained <2.0 x 10(6) CD34+/kg (1.4-1.8). The median engraftment in days (range) was: absolute neutrophil count (ANC) > 500, 12 (9-39); Plt > 20 000, 25 (15-70); RBC transfusion independence, 17 (6-93). Six patients died of progressive disease (58-293 days post-ASCT), one of infection on day 141 and one of AML on day 11. All patients except one maintained ANC > 1000 without filgrastim support beyond day 19. One patient had cholecystitis and delayed graft failure on day 90. PBPC CD34+ content did not predict CD34+ BM content but correlated with ANC > 500 (r= - 0.64, P=0.003). BM and combined CD34+ and BM TNC/kg did not correlate with engraftment or outcomes. Combined CD34+/kg < or > = 2.0 x 10(6) produced similar engraftment and mortality. CONCLUSIONS: After a failed PBPC collection, BM harvest is a reliable option for obtaining an adequate combined autograft. Combined BM-PBPC autografts with <2.0x10(6) CD34+/kg can produce satisfactory engraftment.

Partial HLA matching and RH incompatibility resulting in graft versus host reaction and Evans syndrome after liver transplantation.

We report a case of a 67-year-old male who underwent OLT from a deceased, sex-matched donor. Two months later he developed Evans syndrome and GVHD of the skin. Donor and recipient were matched for HLA-A and -B loci in the direction of rejection but mismatched in the direction of GVHD and fully mismatched for DRB1. These mismatches were permissible for engraftment of donor T-cells but led to GVHD. Chimerism appeared restricted to the T-cell compartment. In this case, partially matched passenger lymphocytes triggered a graft versus host reaction. In addition, alloantibodies caused cytopenias that improved after immunosuppression. HLA typing was critical in confirming this rare diagnosis and elucidating its cause. Recipients of solid organs from donors that are partially matched in the direction of rejection may need to be closely monitored for GVHD.

Graft versus host disease after stem cell allotransplantation with low-dose total body irradiation, fludarabine, and antithymocyte globulin.

BACKGROUND: We previously showed that antithymocyte globulin (ATG) given with total body irradiation (TBI) 200 cGy and fludarabine results in high rate of donor engraftment. Its influence on acute and chronic graft versus host disease (GVHD) and on graft versus tumor effect is less known. METHODS: Sixty-five patients underwent nonmyeloablative stem cell transplant with ATG, TBI 200 cGy, and fludarabine. GVHD prophylaxis was mycophenolate mofetil and cyclosporine. Forty-two patients (pts) (65%) had match related donors, 18 (27%) match unrelated, 1 (1.5%) mismatch related, and 4 (6%) mismatch unrelated donors. RESULTS: At a median follow-up of 862 days, 24 patients (37%) developed GVHD. The median age of the patients with and without GVHD was 56 years respectively. Acute GVHD grade II-IV developed in 19 pts (29%). Fatal GVHD of liver and/or gut occurred in nine pts (14%). Forty-one pts survived more than 100 days. Five pts (12%) had chronic GVHD, two had extensive, and three had limited involvement. Relapsed disease was observed in 22 pts (34%). Infections occurred in 15 pts (23%) and were fatal in 13 (20%). CONCLUSIONS: The addition of ATG to TBI 200cGy and fludarabine resulted in a modest incidence of GVHD. The best transplant outcomes were observed in pts with lymphoid malignancies.

Thrombotic microangiopathy associated with combined sirolimus and tacrolimus immunosuppression after intestinal transplantation.

Calcineurin inhibitor-induced thrombotic microangiopathy (TMA) has been described in up to 14% of solid-organ transplant recipients. Sirolimus has recently been described in two reports in association with TMA. Sirolimus is known to potentiate cyclosporine-induced nephrotoxicity, but such effect has not been shown with tacrolimus. We report two intestinal transplant patients who developed TMA while on a tacrolimus and sirolimus immunosuppressive regimen. This syndrome appeared soon after institution of or increase in sirolimus dosage and improved only after this medication was discontinued.

Retrospective analysis of prognosticators in patients with relapsed Hodgkin's Lymphoma treated with autologous transplant: results of a single center.

Hodgkin's Lymphoma (HL) is highly chemoresponsive, and majority of patients respond to therapy except for a small number which require high-dose therapy and stem cell rescue for salvage. We report the results of a single-center experience in 41 patients with relapsed HL treated with high-dose therapy at the time of relapse from the year 1989-2010. The 7-year OS for the group is 39.2 %; the median progression-free survival is 30.6 months. Univariate analysis identified refractory disease at transplant and extranodal involvement as important prognosticators. The 100-day mortality was 5 %. The most common cause for delayed mortality was disease progression. The incidence of secondary malignancy in the group was 2 %. Our results reinforce the significance of long-term follow up as late relapses are observed. Additionally, identifying biological prognosticators and implying them for treatment may improve the outcomes in poor-risk patients.

Randomized clinical trial of telephone-administered cognitive-behavioral therapy to reduce post-traumatic stress disorder and distress symptoms after hematopoietic stem-cell transplantation.

PURPOSE: A significant number of survivors of hematopoietic stem-cell transplantation (HSCT) report enduring adverse effects of treatment, including illness-related post-traumatic stress disorder (PTSD) symptoms and general distress. We report results of a randomized clinical trial that tested the effects of a 10-session, telephone-administered cognitive-behavioral therapy (CBT) intervention on PTSD, depression, and distress symptoms. METHODS: Survivors who had undergone HSCT 1 to 3 years earlier (N = 408) were assessed for study eligibility. Those who met study eligibility criteria (n = 89) completed a baseline assessment that included a clinical interview and self-report measures of PTSD symptoms (the primary outcome) and depression and general distress (the secondary outcomes). Next, they were randomly assigned to CBT or an assessment-only condition. Survivors in the CBT group completed 10 individual telephone-based CBT sessions (T-CBT) that included strategies to reduce PTSD symptoms, depression, and general distress. Follow-up assessments occurred at 6, 9, and 12 months after the baseline assessment. RESULTS: Linear mixed-model analyses revealed that, compared with HSCT survivors in the assessment-only condition, survivors who completed T-CBT reported fewer illness-related PTSD symptoms, including less avoidance (P < .001) and fewer intrusive thoughts (P < .05) as well as less general distress and fewer depressive symptoms (P < .05) even after controlling for potential demographic and medical covariates. These results were consistent across the three follow-up assessments. CONCLUSION: A brief, telephone-administered CBT intervention developed for HSCT survivors is an efficacious treatment for reducing illness-related PTSD symptoms and general distress.

Primary splenic lymphoma: report of 10 cases using the REAL classification.

Primary splenic lymphoma (PSL) is rare with a reported incidence of less than 1%. Diffuse large cell pathology has been reported in 22-33% of the cases and is felt to have a poor outcome. We report our experience in patients with PSL seen at Mount Sinai Medical Center during the years 1994-1999. Our objective was to evaluate staging (using the Ahmann and Kehoe criteria), prognosis using the International Prognostic Index (IPI), and pathology using the Revised European-American Lymphoma Classification (REAL) classification. Ten patients were identified. Eight of the 10 patients had diffuse large cell lymphoma (DLCL). Using the IPI, four patients were categorized as low risk, three as low/intermediate risk, and three as high risk. The only two deaths occurred in the high-risk group. Lymph node involvement beyond the splenic hilum seen by imaging studies represents an advanced non-Hodgkin's lymphoma and should be included no longer in the staging of PSL. Nine of the 10 underwent a splenectomy. Eight of the nine patients received chemotherapy following splenectomy. Seven of the nine patients remained in remission from 1 to 19 years. Splenectomy followed by combination chemotherapy, results in excellent long-term survival in PSL.

Low-dose total body irradiation, fludarabine, and antithymocyte globulin conditioning for nonmyeloablative allogeneic transplantation.

Nonmyeloablative allogeneic peripheral blood progenitor cell transplantation with low-dose total body irradiation (TBI; 200 cGy) plus fludarabine followed by cyclosporine and mycophenolate mofetil results in modest graft rejection rates. Acute and chronic graft-versus-host diseases (GVHD) are also seen and may not differ substantially from those that occur after fully ablative transplantation. Adding antithymocyte globulin (ATG) to pretransplant conditioning produces substantial immunosuppression. Because of its persistence in the circulation, ATG can achieve in vivo T-cell depletion. Twenty-five patients who were not eligible for conventional fully ablative allogeneic stem cell transplantation by virtue of age or comorbidities underwent nonmyeloablative allogeneic transplantation with ATG 15 mg/kg/d days -4 to -1, TBI 200 cGy on a single fraction on day -5, and fludarabine 30 mg/m(2)/d on days -4 to -2. Oral mycophenolate mofetil 15 mg/kg every 12 hours and cyclosporine 6 mg/kg every 12 hours were started on day -5. Grafts were unmanipulated peripheral blood progenitor cells mobilized with filgrastim 10 microg/kg/d and collected on day 5. The median age of the recipients was 57 years (range, 30-67 years); diagnoses were non-Hodgkin lymphoma (n = 11), acute myeloid leukemia (n = 6), multiple myeloma (n = 3), acute lymphoblastic leukemia (n = 2), severe aplastic anemia (n = 1), paroxysmal nocturnal hemoglobinuria (n = 1), and myelodysplastic syndrome (n = 1). The median CD34(+) and CD3(+) contents of the grafts were 7.6 x 10(6)/kg and 1.6 x 10(8)/kg, respectively. Five patients received voluntary unrelated donor grafts. Three patients, 2 with voluntary unrelated donor grafts and 1 with a sib donor, received a 1 antigen-mismatched graft. The rest were fully matched. Twenty-two of 25 patients were evaluable for chimerism. Sixteen had >/=95% donor chimerism. Four patients displayed 80% to 90% donor chimerism, 1 displayed 78%, and 1 displayed 64%. Eleven patients relapsed with their original disease. One patient rejected the graft at 180 days. The median hospital stay was 27 days. Complications included GVHD in 6 patients (3 patients had grade I or II GVHD of skin and liver, and 3 patients had grade III or IV GVHD of liver and gut). Two of the patients with GVHD had mismatched grafts. Transplant-related toxicity was seen in 4 patients and infection in 5 patients. The median length of follow-up was 162 days (range, 17-854 days). Complete remissions were seen in 10 patients. Four patients remained in complete response (CR) at 280 to 595 days. One patient relapsed with non-Hodgkin lymphoma after a CR of 728 days. Of the 25 patients, 16 died (6 of relapsed disease, 4 of GVHD, 3 of infection, and 3 of transplant-related toxicity) and 9 are alive (6 with CR-2 of them after donor leukocyte infusion-and 3 with relapsed disease). The addition of ATG to low-dose TBI and fludarabine nonmyeloablative conditioning was well tolerated and resulted in >80% donor engraftment in this small cohort. As in other series of truly nonmyeloablative transplantation, a high rate of relapse was observed. Donor engraftment may be facilitated by the addition of ATG to low-dose TBI and fludarabine conditioning.