Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin's lymphoma.

Autologous hematopoietic stem cell transplantation (ASCT) has become standard therapy for primary refractory (PR REF) or relapsed (REL) Hodgkin's lymphoma (HL); however, more than half of these patients eventually relapse and die of their disease. We studied long-term outcomes and evaluated factors influencing progression-free survival (PFS) in 141 patients with PR REF or REL HL who underwent ASCT between 1985 and 2003. Median age at ASCT was 30 years (range, 7-60 years); 21 patients had PR REF, and 120 had REL HL. With a median follow-up of 6.3 years (range, 1-20 years), the probability of PFS at 5 and 10 years was 48% (95% confidence interval [CI], 39%-57%) and 45% (95% CI, 36%-54%) and that of overall survival (OS) was 53% (95% CI, 44%-62%) and 47% (95% CI, 37%-57%), respectively. Transplant-related mortality at 100 days was 1.4%. Among 45 5- to 20-year survivors, no late relapses of HL were observed. In multivariate analysis, 3 factors were independently predictive of poor PFS: chemoresistant disease (relative risk [RR], 2.9; 95% CI, 1.7-5.0), B-symptoms at pretransplantation relapse (RR, 2.1; 95% CI, 1.3-3.4), and presence of residual disease at the time of transplantation (RR, 2.3; 95% CI, 1.1-4.8). Patients with 0 or 1 of these 3 adverse factors (low-risk disease) had a 5-year PFS of 67% (95% CI, 55%-79%) compared with 37% (95% CI, 22%-52%) in those with 2 factors (intermediate-risk group) and 9% (95% CI, 0-20%) in those with all 3 factors (high-risk group) (P < .001). The rates of OS at 5 years were 71% (95% CI, 60%-82%), 49% (95% CI, 33%-65%) and 13% (95% CI, 0-27%) in the 3 groups, respectively (P < .001). ASCT is associated with durable PFS in appropriately selected patients with PR REF or REL HL. Using a simple prognostic model, we can identify patients with high-risk disease who have predictably unfavorable outcome after ASCT and require novel therapeutic approaches. A risk-adapted approach should be followed in determining treatment options for patients with PR REF and REL HL.     

ESHAP salvage therapy for relapsed or refractory non-Hodgkin's lymphoma

The ESHAP regimen, a combination of the chemotherapeutic drugs etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C), and cisplatin, has been shown to be active against refractory or relapsed non-Hodgkin's lymphoma (NHL) in therapeutic trials. We undertook this study to determine whether this regimen would be effective and tolerable in Korean patients. A total of 40 patients with refractory or relapsed NHL (8 indolent and 32 aggressive) were enrolled in this study. The overall response rate was 70% (95% confidence interval; 59.8-89.7%); 22.5% of patients achieved a complete response and 47.5% a partial response. The median survival duration was 12 months (95% confidence interval; 5.9-18.1 months) and the median duration of progression-free survival was 9 months (95% confidence interval; 1.1-16.9 months). The median survival duration of patients with relapsed NHL was longer than that of patients with refractory lymphoma (15 months vs 4 months, p=0.02). Myelosuppression was the most frequent complication and treatment-related mortality was noted in two patients. These results suggest that the ESHAP regimen is effective in patients with relapsed NHL who have a sensitive disease. The role of ESHAP chemotherapy in discriminating patients who are more likely to benefit from a subsequent transplant should be evaluated in the future.     

High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: an effective regimen with low morbidity and mortality.

Over a 10-year period (January 1993 to October 2002), 101 relapsed or refractory non-Hodgkin lymphoma patients were treated at our center with high-dose chemotherapy and autologous transplantation. The median patient age was 54 years (range, 25-70 years). Thirty-two patients had indolent (low-grade), 42 had aggressive (intermediate-grade), and 27 had very aggressive (high-grade) non-Hodgkin lymphoma. Thirty-six patients had primary refractory disease, 20 had a chemoresistant relapse, 35 patients had a chemosensitive relapse, and 10 patients were "initial high risk" patients. The median number of prior chemotherapy regimens was 2 (range, 1-5). The preparative regimen (BEP) was bischloroethylnitrosourea (BCNU) 600 mg/m 2 , etoposide 2400 mg/m 2 , and Platinol (cisplatin) 200 mg/m 2 given intravenously over 5 days. Within 3 weeks before transplantation, 70 patients received involved-field radiotherapy (IFR) 20 Gy to sites of currently active (>2 cm) or prior bulky (>5 cm) disease. Most patients (n = 93) received mobilized peripheral blood stem cells (median CD34 + cell dose, 6.7 x 10 6 /kg). Median neutrophil (>500/microL) and platelet (>20 000/microL, untransfused) recoveries were 11 days (range, 7-19 days) and 14 days (range, 7-36 days), respectively. At a median follow-up of 41 months (range, 4 to 118 months) for survivors, Kaplan-Meier 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 58.6% and 51.1%, respectively. Four patients (4%) died within 30 days of stem cell infusion (1 pulmonary embolism, 2 septicemias with multiorgan failure, and 1 progressive lymphoma). Two patients (2%) developed interstitial pneumonitis most likely secondary to high-dose BCNU. Three cases (3%) of secondary acute myelogenous leukemia occurred. On multivariate analysis, age (<60 or > or =60 years), histologic grade (low versus intermediate or high), the use of IFR, and chemotherapy response at baseline did not affect OS or DFS. Of 70 patients given IFR, 27 relapsed: 10 (37%) within and 17 (63%) outside the radiation field. The use of IFR did not affect either OS or DFS, probably because IFR was offered to patients with bulky or chemoresistant disease. BEP with or without IFR is a highly effective and well-tolerated regimen in the relapsed/refractory lymphoma setting. It has low morbidity and transplant-related mortality and a low incidence (3%) of posttransplantation malignancy.     

Nonmyeloablative unrelated donor hematopoietic cell transplantation to treat patients with poor-risk, relapsed, or refractory multiple myeloma.

The purpose of this study was to determine long-term outcome of unrelated donor nonmyeloablative hematopoietic cell transplantation (HCT) in patients with poor-risk multiple myeloma. A total of 24 patients were enrolled; 17 patients (71%) had chemotherapy-refractory disease, and 14 (58%) experienced disease relapse or progression after previous autologous transplantation. Thirteen patients underwent planned autologous transplantation followed 43-135 days later with unrelated transplantation, whereas 11 proceeded directly to unrelated transplantation. All 24 patients were treated with fludarabine (90 mg/m(2)) and 2 Gy of total body irradiation before HLA-matched unrelated peripheral blood stem cell transplantation. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. The median follow-up was 3 years after allografting. One patient experienced nonfatal graft rejection. The incidences of acute grades II and III and chronic graft-versus-host disease were 54%, 13%, and 75%, respectively. The 3-year nonrelapse mortality (NRM) was 21%. Complete responses were observed in 10 patients (42%); partial responses, in 4 (17%). At 3 years, overall survival (OS) and progression-free survival (PFS) rates were 61% and 33%, respectively. Patients receiving tandem autologous-unrelated transplantation had superior OS and PFS (77% and 51%) compared with patients proceeding directly to unrelated donor transplantation (44% and 11%) (PFS P value = .03). In summary, for patients with poor-risk, relapsed, or refractory multiple myeloma, cytoreductive autologous HCT followed by nonmyeloablative conditioning and unrelated HCT is an effective treatment approach, with low NRM, high complete remission rates, and prolonged disease-free survival.     

Tandem autologous stem cell transplantation for patients with primary refractory or poor risk recurrent Hodgkin lymphoma.

Although autologous stem cell transplantation (ASCT) for patients with relapsed/refractory Hodgkin lymphoma (HL) appears to offer a survival advantage over conventional therapy, only approximately 25% to 35% of patients with primary progressive or poor-risk recurrent HL can achieve durable remission after ASCT, with disease progressive after transplant accounting for most of the treatment failures. We conducted a pilot study to evaluate the toxicities and efficacy of a tandem transplant approach in this subgroup of patients. Between April 1998 and March 2000, 46 patients were enrolled in the study. Eligibility criteria: primary progressive (n = 28) or recurrent HL (n = 18) with at least 1 of the following poor prognostic factors: first complete remission (CR) <12 months (n = 15) or extra-nodal disease (n = 4) or B symptoms at relapse (n = 4). The first cycle consisted of melphalan (150 mg/m(2)) alone. The second cycle consisted of fractionated total body irradiation (FTBI) 1200 cGy or BCNU (450 mg/m(2)) in combination with etoposide (60 mg/kg) and cyclophosphamide (100 mg/kg). Of the 46 patients, 5 (11%) did not receive the planned tandem transplants because of inadequate stem cell collection for 2 ASCT. After a median of 64 days (25-105), 41 patients received the second ASCT. With a median follow-up of 5.3 years (1.6-8.1), the 5-year estimate of overall survival, progression-free survival, and freedom from progression were 54% (95% confidence interval [CI] 40%-69%), 49% (95% CI, 34%-63%), and 55% (95%CI, 40%-70%), respectively. Our mature results from this study suggest that in patients with primary progressive or poor risk recurrent HL, this tandem ASCT program is effective and well tolerated and compares favorably with the conventional single transplant.     

Nonmyeloablative stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia in patients 60 years or older.

We analyzed the outcomes of 24 consecutive patients aged >or=60 years with poor-prognosis myelodysplastic syndrome or acute myeloid leukemia undergoing transplantation with nonmyeloablative conditioning using fludarabine (125 mg/m2) and low-dose total body irradiation (2 Gy) followed by allogeneic peripheral blood stem cell grafts from HLA-identical sibling donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The median age of the patients was 64 years (range, 60-71 years). In addition to age, 88% of patients had 1 or more adverse biological features of the disease. With a median follow-up of 21 months, 12 patients are alive, 11 of whom are disease free. The probabilities of 2-year overall and progression-free survival were 52% and 44%, respectively. The cumulative probabilities of relapse and of acute and chronic GVHD were 27%, 45%, and 74%, respectively. Nonrelapse mortality at 100 days and 2 years was 8% and 25%, respectively. Of the 15 patients with extensive chronic GVHD, 1 patient relapsed. These data suggest that nonmyeloablative stem cell transplantation is a feasible treatment option in patients aged >or=60 years with poor-prognosis myelodysplastic syndrome or acute myeloid leukemia. The reasonable disease control with nonmyeloablative transplantation in this high-risk group of patients merits further investigation.     

High-dose chemotherapy plus non-cryopreserved autologous peripheral blood stem cell transplantation rescue for patients with refractory or relapsed Hodgkin disease.

A simplified schedule of high-dose chemotherapy consisting of cyclophosphamide (60 mg.kg(-1).d(-1) for 2 days), etoposide (15 mg.kg(-1).d(-1) for 2 days), and carboplatin (400 mg/m(2) per day for 2 days) plus autologous non-cryopreserved peripheral blood stem cells (PBSCs) was used for treatment of patients with relapsed (n = 25) and refractory (n = 3) Hodgkin disease. The use of such PBSCs mobilized by granulocyte colony-stimulating factor after high-dose myeloablative therapy resulted in a rapid, complete, and sustained hematopoietic recovery. The median time to achieve an absolute neutrophil count >0.5 x 10(9)/L was 13 days (range, 7-18 days). The median time to a self-sustained platelet count >20 x 10(9)/L was 15 days (range, 7-20 days). Twelve of the 28 patients (43%) were alive and without disease at a median follow-up of 16 months (range, 9-86 months) for all surviving patients. The estimated 2-year overall survival and disease-free survival for all patients were 45% and 42%, respectively. Thirteen patients died of relapse or progressive disease, 2 died of infection, and 1 was still surviving in relapse by the time of the analysis. The median time to relapse was 10 months (range, 3-28 months) from PBSC infusion. High-dose chemotherapy with short-duration chemotherapy and non-cryopreserved bone marrow is an effective and safe treatment modality for patients with relapsed or resistant Hodgkin lymphoma.     

High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin's lymphoma.

No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP ( n = 13) or with ESHAP ( n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31%) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL.     

Ifosfamide, idarubicin, and etoposide in relapsed/refractory Hodgkin disease or non-Hodgkin lymphoma: a salvage regimen with high response rates before autologous stem cell transplantation.

To achieve long-term disease-free survival, high-dose therapy and autologous stem cell transplantation (ASCT) is the current standard approach in patients with relapsed or refractory Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL). Because chemosensitivity is a significant factor in determining transplantation eligibility, it is critical to select a salvage chemotherapy regimen that has the potential to induce a high response rate with low nonhematologic toxicity. In this phase II study, 49 patients with relapsed or refractory HD (n = 22) and NHL (n = 27) with a median age of 42 years were treated with an IIVP salvage regimen consisting of ifosfamide, idarubicin, and etoposide. Twenty-seven percent of the patients had primary refractory disease, whereas 22% and 51% had early and late relapses, respectively. As analyzed by intention to treat, 16 patients (33%) achieved complete remission and 21 patients (43%) achieved a partial response, leading to an overall response rate of 76% (63% in NHL and 91% in HD). In the univariate analysis, diagnosis (HD versus NHL), remission duration before the initiation of IIVP, disease bulk, increased lactate dehydrogenase, and the presence of "B" symptoms were significant factors affecting the response achieved by the IIVP regimen. Of 37 responders, 31 (84%) underwent high-dose therapy and transplantation. The probability of 4-year overall survival (OS) and event-free survival (EFS) in this group of patients who underwent ASCT was 67.7% and 49.1%, respectively. When compared with the patients who achieved a partial response, patients who achieved complete remission with the IIVP regimen had a significantly higher probability of 4-year EFS (67.3% versus 30%; P = .016) and 4-year OS (92.3% versus 39.2%; P = .003). In patients with HD, 4-year EFS and 4-year OS were 54.9% and 70.6%, respectively, without a significant difference with respect to the survival rates obtained in patients with NHL (43.6% and 63.6%, respectively). Common side effects observed during 102 cycles of therapy were grade 3 to 4 neutropenia (62%) and thrombocytopenia (58%). The IIVP regimen is a highly effective salvage regimen for patients with relapsed or refractory HD or NHL who are candidates for ASCT. Furthermore, the degree of response to IIVP predicts the posttransplantation outcome. However, close follow-up is necessary because of a high incidence of grade 3 to 4 hematologic toxicity.     

Autologous hematopoietic stem cell transplantation for mantle cell lymphoma.

This study evaluated the outcomes of patients who underwent high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (autoHSCT) for mantle cell non-Hodgkin's lymphoma and the effect of clinical and treatment characteristics. The clinical outcome and prognostic factors in 40 patients who underwent HDC and autoHSCT for mantle cell lymphoma between June 1991 and August 1998 were analyzed. With a median follow-up of 24 months for the surviving patients (range, 4-68 months), the 2-year overall survival was 65% and the 2-year event-free survival (EFS) was 36%. In univariate analysis, characteristics predictive of a poor EFS were blastic morphology (P = .019) and the patient having received 3 or more prior chemotherapy regimens (P = .004). In a multivariate analysis, the only factor associated with a poor EFS was the number of prior chemotherapy regimens. Those patients who received 3 or more prior therapies had a 2-year EFS of 0%, and those who received <3 therapies had a 2-year EFS of 45% (P = .004). Patients with mantle cell lymphoma can obtain prolonged EFS with HDC and autoHSCT; however, this strategy for prolonged EFS appears to work optimally in patients who are less heavily pretreated. Whether this therapy will increase the overall survival or EFS in patients receiving transplants in first complete remission will need to be tested in prospective randomized clinical trials.     

Phase II study of autologous transplantation with interleukin-2-incubated peripheral blood stem cells and posttransplantation interleukin-2 in relapsed or refractory non-Hodgkin lymphoma.

Previous work suggested that interleukin (IL)-2 can be used for eradicating residual disease in autologous grafts and for preventing recurrence. We report a phase II study of autologous peripheral blood stem cell transplantation with in vitro IL-2 incubation of peripheral blood stem cells and posttransplantation IL-2 in patients with recurrent or refractory non-Hodgkin lymphoma. Salvage chemotherapy consisted of ifosfamide and etoposide. Responding patients underwent autologous peripheral blood stem cell transplantation. IL-2-incubated stem cells were infused on day 0. IL-2 1 mIU/m2 was given from day 1 until day 28. Four monthly maintenance cycles of IL-2 4 mIU/m2 subcutaneously twice daily days 1 to 5 and days 8 to 11 were administered thereafter. Eighty-four evaluable patients were enrolled, and 60 proceeded to transplantation, of which 56 received IL-2-incubated stem cells. The average received dose of posttransplantation IL-2 was 30% to 50% of planned. Only 42 patients received maintenance IL-2. The average received maintenance dose of IL-2 was also approximately 30% of planned. Most dose reductions were due to toxicity or patient refusal. Three-year survival and progression-free survival for all registered patients were 43% (95% confidence interval [CI], 33%-53%) and 31% (95% CI, 21%-41%), respectively. For the 60 patients undergoing transplantation, they were 59% (95% CI, 46%-72%) and 44% (95% CI, 31%-57%), respectively. There was no relation between the dose of IL-2 received and outcome. Survival and disease-free survival of the study group were similar to those of a previous study cohort that received unmanipulated stem cells and no systemic IL-2. Administration of IL-2-incubated peripheral blood stem cells and intensive posttransplantation IL-2 was associated with considerable but rapidly reversible toxicity. No effect on long-term outcome was observed.     

Effectiveness of bendamustine in relapsed or refractory lymphoma cases: a Turkish Oncology Group study

IntroductionWe aimed to investigate the efficacy and side effects of bendamustine in relapsed/refractory lymphoma patients in Turkey.Material and methodsIn this retrospective study, we included relapsed/refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients who underwent multiple lines of chemotherapy. The primary endpoint was to determine the objective response and toxicity.ResultsNinety-nine patients with a median age of 59.8 years were included in the study. Eighty-one patients had NHL (follicular lymphoma: 10, diffuse large B-cell lymphoma: 27, mantle-cell lymphoma: 18, marginal zone lymphoma: 9, small lymphocytic lymphoma/chronic lymphocytic leukemia: 17) and 18 patients had HL. The patients had previously received a median of three lines of chemotherapy (range: 2–8) except autologous stem cell transplantation (ASCT); 19 patients (HL: 11, NHL: 8) had undergone ASCT. The objective response rate (ORR) was 74.3%, the complete response rate was 57% (= 53), and the partial response rate was 16.6% ( = 19). The overall survival (OS) rate at 1 year was 74.6%. The progression-free survival (PFS) rate at 1 year was 62.5%. The most common side effects were lymphopenia, anemia and neutropenia. Side effects which were observed as grade 3 and higher levels were lymphopenia (14.1%), neutropenia (10.1%) and fatigue (7.1%).ConclusionsObjective response rate of bendamustine was found to be 74.3% in relapsed/refractory HL and NHL patients. It appears to be an effective option as a salvage treatment for patients who have previously received multiple lines of therapy.     

Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation.

Allogeneic progenitor cell transplantation is the only curative therapy for patients with refractory acute myelogenous leukemia or myelodysplastic syndromes. To identify prognostic factors in these patients, we performed a retrospective analysis of transplantation outcomes. Patients were selected if they had undergone an allogeneic transplantation between January 1988 and January 2002 and were not in remission or first untreated relapse at the time of transplantation. A total of 135 patients were identified. The median age was 49.5 years (range, 19-75 years). At the time of transplantation, 39.3% of patients had not responded to induction therapy, 37% had not responded to first salvage therapy, and 23.7% were beyond first salvage. Forty-one patients (30%) received unrelated donor progenitor cells. Eighty patients (59%) received either a reduced-intensity or a nonmyeloablative regimen. A total of 104 (77%) of 135 patients died, with a median survival time of 4.9 months (95% confidence interval, 3.9-6.6 months). The median progression-free survival was 2.9 months (95% confidence interval, 2.5-4.2 months). A Cox regression analysis showed that Karnofsky performance status, peripheral blood blasts, and tacrolimus exposure during the first 11 days after transplantation were predictive of survival. These data support the use of allogeneic transplantation for patients with relapsed or refractory acute myelogenous leukemia/myelodysplastic syndromes and suggest that optimal immune suppression early after transplantation is essential for long-term survival even in patients with refractory myeloid leukemias.     

A new schedule of CHOP/rituximab plus granulocyte-macrophage colony-stimulating factor is an effective rescue for patients with aggressive lymphoma failing autologous stem cell transplantation.

From 1999 to 2002, 20 patients with aggressive non-Hodgkin lymphoma, among 28 who failed autologous peripheral blood progenitor cell transplantation, were rescued with cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisone (CHOP)/rituximab (RTX) and granulocyte-macrophage colony-stimulating factor (GM-CSF). RTX was administered twice during each course of chemotherapy, before CHOP and after GM-CSF. This cytokine was given to increase the antibody-dependent cell-mediated cytotoxicity and to reduce the leukopenia on the basis of our preliminary data, which suggested that this cytokine can upregulate CD20 expression. The relevant (World Health Organization grade 3-4) toxicity mainly consisted of myelosuppression (neutropenia in 60% of patients). Fifteen patients achieved complete remission (CR) or had a partial response, with an overall response rate of 75% (60% CR and 15% partial response). Six of the 12 patients who achieved CR relapsed: 2 died of progressive disease, 1 died of infectious complications after allogeneic transplantation, and 3 are alive in second CR. Eight patients showed progressive disease: 5 died of progressive disease, 1 of secondary acute leukemia, and 1 of infectious complications after allogeneic transplantation, whereas 1 is alive in second CR. At last follow-up, 10 patients are alive, 6 of whom are in complete continuous remission, with a median follow-up of 31 months (range, 3-51 months). The projected 4-year progression-free survival is 31.4%, and the 4-year overall survival is 50%. This new association (RTX, CHOP, and GM-CSF) was feasible in approximately 70% of patients; the overall toxicity was manageable. The good response rate and the promising outcome observed in this subset of patients could be explained by the possible increased synergy between chemotherapy, RTX, and GM-CSF, which should be explored in further studies.     

Early stem cell transplantation for refractory acute leukemia after salvage therapy with high-dose etoposide and cyclophosphamide.

Primary refractory acute leukemia (AL) has a poor prognosis, although some patients can be salvaged with allogeneic stem cell transplantation (SCT). Induction of complete remission (CR) with conventional chemotherapy before SCT may improve outcome in this patient population. Between March 1991 and October 2003, 59 adults with primary refractory AL were treated with continuous-infusion etoposide (VP) 2.4 to 3.0 g/m(2) followed by cyclophosphamide (Cy) 6.0-7.2 g/m(2) intravenously over 3 to 4 days with the intention of proceeding to SCT in CR1. Forty-two patients had acute myelogenous leukemia (AML), 13 patients had acute lymphoblastic leukemia (ALL), and 4 patients had acute biphenotypic leukemia. The most frequent nonhematologic toxicities were oral mucosal, gastrointestinal, and hepatic toxicities (44%, 20%, and 15% of patients, respectively). Thirty-two (57%) of 56 evaluable patients entered CR1 with a median time to platelet and neutrophil recovery of 22 and 26 days, respectively. CR1 rates were similar in AML (54%) and ALL/acute biphenotypic leukemia (67%; P = .52), and analysis of baseline characteristics did not reveal any predictors of response to VP/Cy. Twenty-nine of 32 CR1 patients subsequently underwent SCT (24 allogeneic and 5 autologous). Estimated 5-year event-free survival (EFS) and overall survival for the entire cohort are 23% and 26%, respectively. In the allogeneic SCT group, 5-year EFS was 52% for AML patients and 14% for ALL patients (P = .04), and only male sex was predictive of a favorable outcome (P = .03). VP/Cy is able to induce CR1 in most patients with primary refractory AL with an acceptable toxicity profile. Subsequent allogeneic SCT can lead to long-term EFS in a significant proportion of patients.     

Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study.

The incidence and course of bone density abnormalities following hematopoietic stem cell transplantation are poorly understood and complicated by the impact of multiple factors. Hip, spine, and wrist bone mineral densities (BMDs) were measured in 104 adults (54 women, 54 men; mean age, 40 years [range, 18-64 years]) at 3 and 12 months after allogeneic transplantation. Clinical and laboratory variables were evaluated using univariate and multivariate analyses to determine risk factors for osteoporosis, fracture, and avascular necrosis. At 3 months posttransplantation, combined (male and female) hip, spine, and wrist z scores were -0.35, -0.42, and +0.04 standard deviations, respectively. At 12 months both men and women experienced significant loss of hip BMD (4.2%, P < .0001); changes in the spine and wrist were minimal. The cumulative dose and number of days of glucocorticoid therapy and the number of days of cyclosporine or tacrolimus therapy showed significant associations with loss of BMD; age, total body irradiation, diagnosis, and donor type did not. Nontraumatic fractures occurred in 10.6% of patients and avascular necrosis in 9.6% within 3 years posttransplantation. The decrease in height between pretransplantation and 12 months posttransplantation was significant (P = .0001). Results indicate that loss of BMD after allogeneic stem cell transplantation is common and accelerated by the length of immunosuppressive therapy and cumulative dose of glucocorticoid. An increased incidence of fracture and avascular necrosis may adversely impact long-term quality of life. Prevention of bone demineralization appears warranted after stem cell transplantation.     

Plasmapheresis: an effective therapy for refractory hyperthyroidism in the elderly

Hyperthyroidism in the elderly often presents diagnostic challenges. Elderly patients rarely present with classical signs and symptoms of hyperthyroidism. More commonly, their presentation is ayical which leads to a delay in making a diagnosis. Such delays can sometimes decrease the functional capacity of the affected patient and reduce their chance for recovery. Herein we report a 66-year-old woman whose diagnosis of hyperthyroidism was delayed. Standard therapies were ineffective. Plasmapheresis was performed to control the manifestations of the hyperthyroid state, resulting in improvement in the patient's condition.     

Mesenchymal stem cell transplantation: a potential therapy for oral lichen planus

Oral lichen planus is a type of T cell-mediated autoimmune disease. Satisfactory therapy results are not usually achieved with conventional treatment; however, a new therapy employing T cell immune modulation may treat this disease. Mesenchymal stem cells are multipotent nonhematopoietic progenitor cells that are capable of self-renewal and differentiation into various cell types, including osteocytes and adipocytes. Thus, mesenchymal stem cells are regarded as a promising cell population for tissue regeneration in the clinic. In the past several years, there has been a dramatic improvement in the understanding of immunosuppressive properties of mesenchymal stem cells on various immune cell types. We propose that mesenchymal stem cells can be utilized to treat oral lichen planus patients via systemic infusion or local application.