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PubMedID: 20673585 This prospective multicenter phase III clinical trial was designed to assess efficacy and safety of G-CSF as an adjunct to de novo AML remission induction therapy (www.clinicaltrials.gov. NCT00820976). Patients' characteristics were similar in both arms. G-CSF improved severity and duration of leukopenia. Three-year OS were similar (25.6 ± 5.1% vs. 31.8 ± 5.6%) in both arms except for patients with myeloblastic features. Significant factors for better survival were the use of G-CSF (p= 0.049), female sex (p= 0.05) and single induction cycle (p< 0.001) in multivariate analysis. Female patients performed better than male patients. Better survival obtained among female AML patients needs to be validated within the context of cytogenetic analysis. © 2010 Elsevier Ltd. The authors are indebted to the efforts of all the institutions who participated in the trial and their data management teams. Also the authors would like to thank to all physicians including Dr. Semra Dundar, who died in 2005, and their patients for this collaborative effort. Filgrastim was supplied by Roche, This study was partially supported by the Turkish Academy of Sciences. Monitoring and statistical analysis were performed by an independent clinical research organization (OMEGA, Ankara, Turkey). And a special thank you to the following hospitals and investigators that participated in this trial: Akdeniz University, Antalya, Turkey (L. Undar); Ankara University, Ankara, Turkey (M.B., M.O., O. l., G.G., A.U., H.A., E.A.); Cukurova University, Adana, Turkey (S.P.); Dokuz Eylul University, Izmir, Turkey (B. Undar); Ege University, Izmir, Turkey (S. Cagirgan); Erciyes University, Kayseri, Turkey (A. Unal, M. Cetin); Gulhane Military University, Ankara, Turkey (A. U. Ural, C. Beyan); Hacettepe University, Ankara, Turkey (S. Dundar, O.O., Y.B.); Inonu University, Malatya, Turkey (I. Aydogdu); Istanbul University of Cerrahpasa, Istanbul, Turkey (B. Ferhanoglu); Istanbul University of Istanbul, Istanbul, Turkey (D. Sargin, Sevgi Kalayoglu-Besisik); Marmara University, Istanbul, Turkey (M.B.); Osmangazi University, Eskisehir, Turkey (Z. Gulbas); Uludag University, Bursa, Turkey (A.T., R.A., F.O., T.O.). Contributions : M.B. provided the conception and design of the study, or acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content and final approval of the version to be submitted; M.O., E.A.S. and A.T. provided the conception and design of the study, or acquisition of data, or analysis and interpretation of data and final approval of the version to be submitted; R.A. and T.O. provided the drafting the article or revising it critically for important intellectual content and final approval of the version to be submitted and O.O, M.B., S.P., Y.B., O.I., F.O., G.G., A.U. and H.A. provided the final approval of the version to be submitted.

The purpose of this study was to evaluate the correlation of preleukapheresis circulating CD34+ cells/muL, white blood cells (WBC), and platelet counts on the first day of apheresis with the yield of collected CD34+ cell counts in 40 patients with hematological malignancies (n = 29) and solid tumors (n = 11). The median numbers of apheresis cycles, numbers of CD34+ cells, peripheral blood (PB) mononuclear cells, and total nucleated cells collected were 2 (range, 1-4), 5.5 x 10(6) /kg (range, 0.05-33.78), 2.59 x 10(8)/kg (range, 0.04-20.68), and 7.36 x 10(8)/kg (range, 0.15-28.08), respectively. There was a strong correlation between the number of preleukapheresis circulating CD34+ cells/muL and the yield of collected CD34+ cells per kilogram (r = 0.962, p < 0.001). The threshold levels of PB CD34+ cell/muL to obtain greater than or equal to1 x 10(6)/kg and greater than or equal to2.5 x 10(6)/kg CD34+ cell in one collection were 12/muL and 34/muL, respectively. Fifteen of 17 (88%) patients who had greater than or equal to34 CD34+ cells/muL in the PB before collection reached the level of greater than or equal to2.5 x 10(6)/kg in a single apheresis. Despite a low r value, WBC and platelet counts on the first day of apheresis also correlated with the yield of collected daily CD34+ cells per kilogram (r = 0.482, p < 0.01 and r = 0.496 p < 0.01, respectively). These data suggest that preleukapheresis circulating CD34+ cells/muL correlated significantly better with the yield of collected CD34+ cells than WBC and platelet counts on the first day of apheresis. Using a value of 34/muL preleukapheresis circulating CD34+ cells as a guide for the timing of peripheral blood stem cells collections can be time saving and cost-effective.

We studied the effects of recombinant human granulocyte colony-stimulating factor (G-CSF) on hematopoietic recovery and clinical outcome in patients undergoing allogeneic peripheral blood stem cell (PBSC) transplantation. Fifty-six patients with hematological malignancies who underwent allogeneic PBSC transplantation between 1995 and 1998 were entered into this study. Twenty-eight patients who received daily G-CSF from day +1 after allogeneic PBSC transplantation until the absolute neutrophil count (ANC) reached >0.5 x 10(9)/l for 3 consecutive days were compared with 28 patients (control group) who did not receive G-CSF in a non-randomized manner. The study group and the control group were comparable with respect to baseline patient and transplantation characteristics. Median times to ANC of >0.5 x 10(9)/l and 1 x 10(9)/l with or without G-CSF were 12 days (range 8-21), 13 days (10-32) (P = 0.04) and 13 days (9-21), 15 days (11-44) (P = 0.02), respectively. Median times to reach a platelet count of >20 x 10(9)/l with and without G-CSF were 11 days (0-20) and 13 days (9-26), respectively (P = 0.03). The incidence of febrile episodes was significantly lower with G-CSF, 75% vs 100% (P = 0.008). Patients receiving G-CSF had less grade III-IV mucositis than those who did not receive G-CSF (P = 0.01). There was also no increase in the incidence and severity of acute GVHD in patients using G-CSF (P = 0.22). Although the number of relapsing patients was greater in the G-CSF group (seven vs three patients), this was not statistically significant (P = 0.24). Disease-free and overall survival rates did not differ between the two groups (P = 0.58 and 0.53, respectively). The administration of G-CSF after allogeneic PBSC transplantation provided faster neutrophil and platelet engraftment associated with less severe mucositis and less febrile episodes.

Allogeneic peripheral blood stem cell transplantation (PBSCT) is rarely applied for the treatment of severe aplastic anemia (SAA) because of questionable durability of engraftment and increased risk of graft versus host disease (GVHD). We performed allogeneic PBSCT in 3 SAA patients from their human leukocyte antigen (HLA)–identical siblings. One received bone marrow after conditioning with cyclophoshamide (Cy) plus antithymocyte globulin. He had a second transplant with peripheral blood stem cells from the original donor because of a graft failure (GF). Two other patients received PBSCT as a first option, with Cy as the only conditioning drug. The 3 patients received short-term methotrexate and cyclosporine as a postgrafting immunosupression. In the latter 2 cases, no GF has been observed, and a successful and complete hematological recovery was achieved and maintained for 28 and 25 months, respectively. In conclusion, PBSCT provides a quick and complete hematological recovery in SAA patients.

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 (P0.001). 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.

Two cases with acute myeloblastic leukemia (AML M4-FAB) associated with diabetes insipidus (DI) are presented here. Both patients presented with hyperleucocytosis. One had a white blood cell count (WBC) of 150 x 10(9)/L and the second patient had 200 x 10(9)/L. One of these patients was a 40 year-old male and MRI of the hypophysis showed an infindibuler mass. This patient did not respond to remission induction chemotherapy and reinduction chemotherapy was given. The other patient was a 16-year-old male with a normal CT scan of the head. Both patients had DI with typical clinical and laboratory findings. The first patient died early on during reinduction chemotherapy and the second patient died of intracranial bleeding before induction chemotherapy was given. These findings are consistent with the data in the literature suggesting that the prognosis of AML associated with DI is poor and that these cases generally present with hyperleucocytosis.

Graft versus host disease (GVHD) is one of the obstacles encountered in allogeneic bone marrow transplantation (alloBMT) and has a direct impact on the transplant outcome and survival. In this report, we summarized the incidence of acute and chronic GVHD among 71 HLA matched and 9 HLA mismatched sibling alloBMTs performed for various hematological malig-nancies, mainly leukemias seen at Ibn-i Sina Hospital. Fifty-five were male and 25 were female Turkish patients. Median age was 29 (12-48). Cyclophosphamide(CY) + total body irradiation (TBI)(12), CY + total lymphatic irradiation (TLI)(6), busulfan (BU) + CY(58) and ALG/ATG + CY(4) were the regimens used for conditioning. Cyclosporin A (CsA) + short term methotrexate were given for GVHD prophylaxis except for two syngeneic transplants who both received only CsA. In 22 of the patients ABO and in 30 patients sex mismatched bone marrow was given. Thirty-one (38.8%) patients showed acute GVHD (grade I-II: 22, grade III-IV: 9) and 8 (11.6%) showed chronic GVHD. In HLA matched and mismatched patients acute GVHD incidence were 33.7% and 44.4% respectively. All of the HLA mismatched patients that showed acute GVHD were in advanced stage. Of the patients with acute GVHD, 28 (96.5%) disclosed skin, 22 (75.9%) hepatic and 14 (48.3%) gut involvement. In the chronic form three patients had mild limited, two limited, two moderate and one advanced GVHD. Seven of the patients were lost due to GVHD. To determine the graft versus leukemia effect of alloBMT, we compared the disease free survival (DFS) of the 68 leukemia patients. Although the patients who had grade I-II acute GVHD showed a better DFS than the patients who did not have acute GVHD, it did not reach to a significance (15.9 vs 13.6 months: p=0.43).

The combination of cyclophosphamide (CY) and etoposide is synergistic, spares bone marrow stem cells and can be given repeatedly in high doses without stem cell support. Thirteen patients with non-Hodgkin's lymphoma (n = 8) or Hodgkin's disease (n = 5), received high-dose chemotherapy (HDC). Median age was 32 years (24-52). Male to female ratio was 10:3. All the patients were in advanced-stage. Karnofsky score prior to HDC was 60% (range 40-90). Six patients showed primary refractoriness and 7 had resistant relapse. HDC consisted of CY 1,500 mg/m2/day and etoposide 300 mg/m2/day, both for 4 days. rhG-CSF was started 24 h after the last dose of chemotherapy as a continuous intravenous infusion at a dose of 0.01 mg/kg/day and stopped when the leukocyte count reached 1 x 10(9)/1 on 3 consecutive days. Overall, 69% (9/13) of patients responded to HDC. Four achieved CR and 5 achieved PR. Two of the patients showed disease progression. The other 2 died during the early period of HDC. Neutrophil and platelet recovery after HDC were 8 (6-16) and 10 (4-14) days, respectively. The major nonhematological toxicities were nausea-vomiting (100%) and diarrhea (61%). The median follow-up was 204 (7-600) days. Two patients relapsed 48 and 185 days after HDC. Eight patients are still alive, 7 progression free. The progression-free survival is 220 (40-285) days. In conclusion, HDC + granulocyte colony-stimulating factor (G-CSF), without stem cell support seems to be promising in refractory or resistant relapse lymphoma patients bringing the need for randomized studies to show the cost effectiveness of HDC + G-CSF compared to HDC + autologous stem cell support.

Forty-five patients who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) were evaluated in order to investigate any relationship between CD34+ cell dose given and hematological recovery. Granulocyte counts1.0 x 10(9)/L and platelet50 x 10(9)/L were considered as hematological recovery. Three different regimens were used for mobilization, by adjusting the recombinant granulocyte colony stimulating factor (rhG-CSF, Roche) dose. The first group (n = 3), whose donors mobilized with 5 micrograms/kg/d s.c. rhG-CSF received a mean of 5.9 x 10(6)/kg (95% confidence interval for mean (CI); 2.4-9.3) CD34+ cells. The second group (n = 37), mobilized with 10 micrograms/kg/d s.c. rhG-CSF and the third group (n = 5) mobilized with 15 micrograms/kg/d s.c. rhG-CSF, received a mean of 5.7 x 10(6)/kg (95% CI; 4.6-6.75) and 6.56 x 10(6)/kg (95% CI; 4.57-8.55) CD34+ cells, respectively. CD34+ cell dose was 5.82 x 10(6)/kg (95% CI; 4.97-6.68) for all the patients. All patients received rhG-CSF from day +1 until attaining granulocyte count1.0 x 10(9)/L for three consecutive days. Median granulocyte and platelet engraftment days for the whole group was 15 (range; 11-44) and 14 (11-54) days respectively. There was a close correlation (r = -0.301, p0.05) between the CD34+ cell dose and granulocyte recovery for the whole group. When these analyses were performed separately within groups, this correlation was also found significant for the first group (r = -0.99, p0.05) for granulocyte recovery. On the contrary the same analysis did not reach significance for the other groups, nor for platelet recovery for the whole group (r = 0.039, p = 0.821). We calculated a minimum dose of 4 x 10(6)/kg CD34+ cells for a safe alloPBSCT. There was no difference between patients who received more than 5 x 10(6)/kg CD34+ cells, and those who received more than 2 x 10(6)/kg and less than 5 x 10(6)/kg CD34+ cells. In conclusion, we have demonstrated a correlation between the CD34+ cell dose given and faster hematological recovery for alloPBSCT patients.

Background The effect of allogeneic hematopoietic cell transplantation (alloHCT) on hematologic malignancies is based on the graft-versus-malignancy effect. Obtaining this effect with reduced toxicity has been possible by non-myeloablative (NMA) alloHCT. Once mixed chimeric status, and host versus graft with graft versus host tolerance are achieved, further strengthening of chimerism and graft-versus-malignancy effect can be obtained by donor lymphocyte infusions (DLIs) when needed. Methods The patient group consisted of 13 patients with advanced hematological malignancies: seven had CML, four of them in blastic-, two in chronic- and the remainder in accelerated-phase; four patients with AML, refractory or in second remission state; one patient with primary refractory secondary AML; and one patient with ALL relapsed after alloHCT. Conditioning regimen consisted of fludarabine 30mg/m 2 /day for 6 days and anti-T-lymphocyte globulin (ATG) 10mg/kg/day for 4 days as immunosuppressive. Ara-C or Bu or melphalan were used as the cytoreductive component. All transplants were performed using HLA-identical sibling donors' peripheral blood hematopoietic cells, after priming with filgrastim. Post-transplant GvHD prophylaxis was achieved with CsA alone in 10 patients, and with CsA plus mycophenolate mofetil in the last three patients. Results Median follow-up is 3 months (range, 0–20) for all the patients and 6 months (range, 2–15) for the live patients. Donor chimerism was shown in 10 patients, not regarding any pretransplant feature. DLIs were performed in seven patients after transplantation and two of them achieved complete chimeric status and molecular remission. Two CML patients in blastic phase (CML-BP), and the primary refractory secondary AML patient did not respond to procedure. In four patients, drug therapy in conventional doses was added to post-transplant DLIs for their relapsed or refractory diseases. Two patients with AML in second CR, and another CML-BP patient, relapsed or progressed after transplantation. A patient with CML-BP achieved CR and full donor chimerism after transplantation, but developed refractory posttransplant lymphoproliferative disease in the 19th month. Two patients with refractory AML, one patient with relapsed ALL and two patients with CML in chronic phase were in complete chimeric status and free of disease signs. Acute GvHD, Grade II–III, was observed in five patients, and two of them developed secondary progressive chronic GvHD subsequently. We observed one early death in a platelet transfusion refractory blastic phase CML patient due to intracranial hemorrhage. Procedure-related severe toxicity was not observed, either in standard-risk patients or stem-cell donors . Discussion Establishing engraftment with donor chimerism was the first successful step in this approach. The second step, which was the result of the graft-versus-malignancy effect, could be seen in most of the patients, but was not sustained in all of them because of the aggressiveness of their malignancy. It can be suggested that the immunotherapeutic efficacy of this approach could be more successful, and with acceptable toxicity, when performed in patients with minimal residual disease. The role of NMA conditioning, and of the treatment in standard disease indications, remains to be determined in further studies.

We analysed the effects of rhG-CSF (Amgen-Roche, USA) on serum changes of four soluble adhesion molecules (SAM) (sICAM-1, sL-Selectin, sE-Selectin and sCD44) in healthy peripheral allogeneic stem-cell transplantation donors and their correlation with acute GvHD and effect on engraftment kinetics.Serum SAM of 15 consecutive healthy HLA identical-sibling donors (median age 30 years, male:female ratio, 7:8) were monitored using a commercial ELISA Kit (Bender Med, Austria) prior to, on the day of first apheresis and 24 h after the cessation of rhG-CSF (10 microg/kg/day s.c. on 5 days) administration. Leukapheresis was started on the fifth day of rhG-CSF administration, using a continuous-flow blood separator (Cobe Spectra, COBE BCT, Inc, Lakewood, CO). Apheresis cycles were continued daily until a target of 4.0 x 10(6) CD34(+) cells/kg was reached.The results indicate a steady rise of sL-Selectin, sE-Selectin, and sCD44, but not of sICAM-1. Median number of mononuclear cells (MNC) and CD34(+) cells transfused were 7.7x 10(8)/kg and 6.0 x 10(6)/kg, respectively. There was a near-significant correlation between the sL-Selectin levels and CD34(+) cell yield (r = 0.49, 0.06). Median granulocyte and platelet engraftment days were 11 (10-18) and 12 (9-33), respectively. There was a significant inverse correlation between the CD34(+) cell dose and granulocyte levels (r = -0.68, p = 0.022), but not for platelet engraftment. The only correlation between SAM levels and engraftment was for sICAM-1 levels. Increasing sICAM-1 levels were a sign of prolonged neutropenia (r = 0.72, p = 0.011). No correlation between the apheresis day serum levels of adhesion molecules and acute GvHD was documented.Analysis of sICAM-1, sL-Selectin, sE-Selectin and sCD44 levels during allogeneic PBSC apheresis did not reveal any significant effect on engraftment and GvHD, except the correlation of sL-Selectin levels and collected CD34(+) cells. More research and data about the role of not only SAM levels, but also antigenic expression of SAM are required to enlighten leukocyte-endothelial cell interactions and egress of stem cells during G-CSF administration.

Pericardial involvement, a rare complication of multiple myeloma (MM), is caused by amyloidosis, infections, bleeding abnormalities or plasma cell infiltration, usually at a late or terminal stage of the disease. Three cases of MM with pericardial involvement are reported here and discussed in the light of current literature. In a retrospective review of all patients with MM at two institutions, three cases of pericardial involvement were identified. In one case, we were able to obtain cytospin preparations of the pericardiocentesis fluid. In the remaining two patients, the pericardial biopsy specimen was obtained via a pericardial window. All patients had progressive dyspnea and signs of pericardial tamponade. The pericardiocentesis fluid showed infiltration with plasma cells in one of the three patients, who had a progressive and fatal course. In the second patient pericardial invasion was proven by biopsy and the third was diagnosed with a plasma cell leukemia but developed a pericardial effusion demonstrated by pericardial biopsy. All these three patients died of progressive disease without any response to chemotherapy and supportive measures. In conclusion, optimal treatment for malignant involvement of the pericardium by myeloma cells has not yet been established and is often fatal.

Fifty-three patients with standard risk leukemia who underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) from their HLA-identical siblings were analyzed for engraftment, incidence and severity of GVHD, and relapse rate. Standard risk leukemia was defined as AML in first complete remission or CML in first chronic phase within the first year after diagnosis. The median age was 34.5 years (range 13-47). Stem cells were mobilized by using 10 microg/kg G-CSF subcutaneously for 5 days. A median of 5. 7 (2.1-21.4) x 106/kg CD34+ cells was collected over a median of 2 (range 1-5) apheresis procedures. Cyclosporin A (CsA) plus short-course MTX were used for GVHD prophylaxis. Recovery to granulocytes0.5 x 109/l and platelets20 x 109/l occurred at a median of day +13 (range 8-32) and +13 (range 8-51), respectively. Day +100 transplant-related mortality was 13.2% (7/53). Acute GVHD occurred in 20 of 49 (41%) evaluable patients and only six (12.3%) of them had severe disease (grade III-IV). Chronic GVHD occurred in 30 of 42 (71.4%) evaluable patients. Relapse rate at 2 years was 7. 5%. The median overall and leukemia-free survivals were 22 (4-44) and 20 (3-44) months, respectively. Estimated 4 year leukemia-free and overall survival rates were 60% and 62%, respectively. In conclusion, alloPBSCT in standard risk leukemia seems to be associated with a low relapse rate and no increased risk of acute GVHD, but there is a trend for higher incidence of cGVHD. Bone Marrow Transplantation (2000) 25, 1229-1232.

The purpose of this study was to determine the maximum tolerated dose of carboplatin administered with 500 mg/m(2) thiotepa and 100 mg/m(2) melphalan followed by autologous peripheral blood stem cell (PBSC) infusion in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose thiotepa (500 mg/m(2), melphalan (100 mg/m(2)) and escalating doses of carboplatin 900-1500 mg/m(2)) followed by infusion of cryopreserved autologous PBSCs, The maximum tolerated doses were determined to be 500 mg/m(2) thiotepa, 100 mg/m(2) melphalan and 1350 mg/m(2) carboplatin. Two consecutive patients receiving 1500 mg/m(2) carboplatin experienced grade 3 mucositis and colitis, Ten patients were enrolled at the maximum tolerated dose and none had grade 3-4 regimen-related toxicity and mortality. All patients at this level experienced grade 1-2 mucositis, 90% grade 1-2 gastrointestinal toxicity, 30% grade 1-2 cardiac and renal toxicity, and 10% experienced grade 1 hepatic toxicity, The median time to achieve a granulocyte count of 0.5 x 10(9)/l was 9 days (range 7-12 days) and platelet count of 20 x 10(9)/l was 10 days (range 7-15 days), Of eight patients with stage IV refractory breast cancer, even were evaluable for response, one patient on day 75 will be evaluated soon. Five of seven (71.5%) evaluable patients achieved a complete remission (CR) and two had no response. Of seven patients with non-Hodgkin's lymphoma (n = 4) or Hodgkin's disease (n = 3), five achieved a CR (71.5%). Thiotepa, melphalan and carboplatin can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy-sensitive malignancies are warranted.

Background/Aims: Hepatitis B virus can cause serious problems in individuals undergoing organ transplantation. The aim of this study was to evaluate the hepatic events among HBs-Ag positive recipients and HBs-Ag negative recipients who received products from hepatitis B virus carriers. Methods: A total of 151 patients received an allogeneic hematopoietic stem cell transplantation at the Department of Hematology-Oncology, University of Ankara, between June 1989 and June 1998. Among these, eight HBs-Ag positive and four HBs-Ag negative recipients received a product from a hepatitis B virus positive donor. The median follow-up period for these 12 patients was 13.2 months. Results: Three of the eight HBs-Ag positive recipients died (one from hepatic failure); of the remainder, two are HBs-Ag negative, two HBs-Ag positive with normal liver injury tests and one HBs-Ag positive with elevated ALT levels. Of the four HBs-Ag negative recipients who received stem cells from a hepatitis B positive donor, two died; none of the patients in this group became HBs-Ag positive after transplantation. Conclusion: Hepatitis B virus infection is a common problem in patients being considered for allogeneic hematopoetic stem cell transplantation, especially in areas where hepatitis B virus infection is endemic. We believe that the presence of HBs-Ag positivity is not an absolute contraindication for allogeneic hematopoetic stem cell transplantation unless the hepatitis B virus is in a replication phase.

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 micrograms/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) x 10(8)/kg MNC or 9.4 (2.2-12.4) x 10(6)/kg CD34+ cells were given. Median days to reach granulocyte of > 0.5 x 10(9)/l and platelet of > 50 x 10(9)/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.

To detect the effect of the stem cell source, allogeneic peripheral blood stem cell transplantations (alloPBSCTs) performed between 1995 and 1997 from human leukocyte antigen (HLA)-identical siblings in 40 patients with acute and chronic hematological disorders were compared with a historical group of 40 patients with similar variables who had received allogeneic bone marrow transplants (alloBMTs) between 1993 and 1995. Patients in both groups were identical except that both the recipient and the donor ages were, on average, higher in the alloPBSCT group (26 vs. 36 [p = 0.005] and 27 vs. 32 [p = 0.024], respectively). Patients received similar therapy excluding posttransplant granulocyte colony-stimulating factor administration (97% in alloBMT vs. 12.5% in alloPBSCT). The median time to reach neutrophil counts >0.5 x 10(9)/L and platelet counts >20 x 10(9)/L was 13 and 14 days, respectively, in patients receiving alloPBSCTs compared with 19 and 27 days in patients receiving alloBMTs (p = 0.0014 and p=0.0002). The alloPBSCT group required similar transfusions of red blood cells or platelets. The incidence of grade II-IV acute graft-vs.-host disease (aGVHD) was similar in both groups. However, chronic GVHD (cGVHD) of all grades developed in 78.1% of patients in the alloPBSCT group after a median follow-up period of 12.5 (range 0.5-34) months. In alloBMT recipients, cGVHD of all grades developed in 21.4% after a median follow-up period of 38 (range 0.5-62) months (p = 0.00001). Day 100 transplant-related mortality was also similar: 20% (8 of 40) in the alloBMT patients and 17.5% (7 of 40) in the alloPBSCT group. Although not statistically significant, a relatively higher relapse rate occurred in the alloBMT group (21.4 vs. 10.7%). The estimated disease-free survival in month 24 was 51.3% for alloBMT and 54.6% for alloPBSCT, and the estimated overall survival in month 24 was 56.1% for alloBMT and 64.6% for alloPBSCT. In conclusion, this retrospective comparison suggests that alloPBSCT from HLA-identical donors is associated with faster engraftment, fewer transfusions, and no greater incidence of aGVHD, but a high incidence of cGVHD. Biol Blood Marrow Transplant 1999;5(1):28-35.

Fourty-four patients who underwent allogeneic bone marrow transplantation (alloBMT) were studied for hepatitis B virus (HBV)-related complications. The mean follow-up period was 15.3 months. Positivity for HBV surface antigen (HBsAg) was observed in 10 patients (22.7%) throughout the study. Four of the 10 patients were HBsAg carriers before alloBMT, while the remaining six became HBsAg(+) after alloBMT. During the follow-up period (from 6 months to 45 months), an elevation in serum ALT activity was observed in the four carriers when immunosuppression was reduced or withdrawn. All of the four HBsAg carriers developed hepatitis, but none of them died of liver failure due to HBV. Only one death due to GVHD and diabetic ketoacidosis was observed in this group. Two of the four carriers received marrow from anti-HBs positive donors and one of them cleared HBsAg from his serum via adoptive immunity 8 months after transplantation. The remaining six patients acquired HBV after alloBMT, but we were unable to demonstrate the source of HBV. Five of them had a moderate increase in serum ALT activity while the other patient had a normal ALT. Two patients seroconverted to anti-HBs spontaneously. Two patients died during the follow-up, one due to intracranial hemorrhage and the other due to GVHD and accompanying pulmonary infection. The rest of the study group (34 patients) remained HBsAg(-) throughout the study. Two of them had an HBsAg(+) donor, but neither developed HBV infection in their follow-up period. The acquisition rate of HBV infection was relatively low in recipients who were positive for anti-HBs compared to those who were negative for anti-HBs (8 vs 19%). Anti-HBs positivity remained for a longer period in recipients who received marrow from anti-HBs positive donors compared to those recipients who had anti-HBs negative donors (median 12 vs 3 months). We think that HBV is a frequent cause of liver dysfunction in alloBMT patients where HBV infection is endemic. Whether the disease is in the form of reactivation of HBsAg-positive recipients, or is acquired from unknown sources in recipients who never had contact with the virus, the course of the disease is not fatal. Silent serologic changes can be demonstrated if viral serologic markers are sought serially. Among them, the disappearance of serum anti-HBs may be important as it increases the risk of HBV contamination in recipients.

Hemorrhagic cystitis (HC) is one of the most troublesome complications of bone marrow transplantation (BMT) and sometimes may be life-threatening. The etiology and prevalence of HC depends on the type of the transplant and the period after BMT. Here we report about 134 patients transplanted in a single center (89 allogeneic and 45 autologous) between May 1988 and August 1995. Forty-six patients (34.3%) had HC after BMT. Thirty-four (38%) alloBMT patients and 12 (27%) autoBMT patients had HC (p = 0.18). The onset of HC was 7 to 125 days after transplantation. The degree of HC was mild to moderate in 25 (28%) and severe in 9 (10%) allogeneic transplants. In autologous transplants, all of the episodes of HC were mild to moderate. Age, sex, diagnosis and the dosage of mesna used for prophylaxis were not correlated with the incidence of HC. In 36 of 46 (78.2%) patients HC occurred early and as a transient form. Ten (21.7%) were late and long-lasting. In 2 patients who had late starting and long-lasting HC after allogeneic BMT, electron microscopic examinations revealed virus-like structures in bladder epithelial cells.