Continuous infusion cyclophosphamide and low-dose total body irradiation is a safe and effective conditioning regimen for autologous transplant in multiple myeloma.

We present the results of a novel conditioning regimen in multiple myeloma (MM) patients undergoing tandem autologous stem cell transplant (ASCT). MM patients were enrolled in a prospective phase II clinical trial. After initial ASCT, disease response was assessed by day +100. Patients achieving very good partial remission (VGPR) were offered maintenance therapy. If patients achieved VGPR, they were offered a second ASCT using continuous intravenous cyclophosphamide (CICy) 6 g/m(2) over 4 days and low-dose total body irradiation (ldTBI) 600 rads over 2 days. Total body irradiation was replaced by melphalan 140 mg/m(2) if patients had received prior radiation. Twenty-one patients received tandem ASCT. Three patients received CICy and melphalan. Median duration of neutropenia with CICy/ldTBI was 11 days. Fifteen patients (71.4%) developed febrile neutropenia while grade 1 to 2 diarrhea was the next most common adverse event (42.9%). There was no treatment-related mortality. Four patients had entered complete remission (19%) and 6 achieved VGPR (28.6%). In conclusion, this conditioning regimen is safe and effective and may be useful in patients who do not benefit from first ASCT using more traditional conditioning regimen.

Extramedullary disease in plasma cell myeloma: the iceberg phenomenon.

Extramedullary (EM) plasmacytomas (EMPs) that are not progression of intramedullary (IM) plasma cell myeloma (PCM) are usually indolent. In contrast, EM spread of IM PCM is associated with a poor prognosis. The recently introduced Durie-Salmon PLUS staging system includes EM disease in the poor prognosis category. One study noted an increase in EM disease both at diagnosis and during follow-up of PCM in 2000-2007 compared with previous years raising concerns that adoption of novel agents (thalidomide, lenalidomide and bortezomib) and greater use of hematopoietic cell transplantation (HCT) might be contributory to this. It is uncertain if this is a true increase or merely greater detection due to the increasing use of more sensitive imaging techniques (computerized tomography, magnetic resonance imaging and ¹8F-fluorodeoxyglucose positron emission tomography) or a reflection of the evolving natural history of PCM in an era when patients are living longer (median overall survival before 1996 was 29.9 months vs 44.8 months after 1996). Recent studies suggest there are important biological differences between PCM with or without EM spread that are offering clues that might explain the propensity for dissemination and a more aggressive clinical course. For example, EM relapse in PCM with and without deletion 13 was 30.8 vs 5.6%, suggesting the biology of a plasma cell subclone before HCT can affect the nature of the relapse after HCT. This article will explore the clinical, biological and treatment implications of EM spread of PCM. In addition, the impact of extramedullary disease on the outcomes of autologous and allogeneic HCT for PCM will be analyzed. Allogeneic HCT early in the course of high-risk PCM with EM disease is a consideration since graft vs myeloma effects may be essential to achieve maximal survival benefits.

Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw.

Bisphosphonate induced osteonecrosis of the jaw (BONJ) is a complication in patients taking bisphosphonate (BP) that affects their quality of life and compliance. In this cohort study, patients with multiple myeloma (MM) on intravenous BP therapy were enrolled over 1 year. Demographic and clinical data and genotyping of 10 single nucleotide polymorphisms (SNPs) from seven candidate genes associated with drug or bone metabolism were determined. Of the 78 patients enrolled, 12 had BONJ. The median time to developing BONJ was 28 months. Univariate and multivariate analysis revealed a significant association between BONJ and smoking (p=0.048) and type of BP treatment (p=0.03). A trend for higher odds for BONJ was found for SNPs in five genes: COL1A1 (rs1800012), RANK (rs12458117), MMP2 (rs243865), OPG (rs2073618) and OPN (rs11730582). Considering all five SNPs together, patients with genotype scores ≥ 5 had a BONJ event rate of 57%; those with scores < 5 had a rate of 10%. The adjusted odds ratio was 11.2 (95% confidence interval of 1.8-69.9; p value 0.0097). Smoking, type of BP and combined genotype score of COL1A1, RANK, MMP2, OPG and OPN were significantly associated with BONJ in MM patients undergoing BP therapy.

Six cases of permanent alopecia after various conditioning regimens commonly used in hematopoietic stem cell transplantation.

Alopecia, a side effect of chemotherapy, is usually temporary and reversible. Irreversible alopecia has been reported after high-dose chemotherapy (HDC) and hematopoietic stem cell transplantation (HSCT) especially related to BuCy containing conditioning regimens; however, the overall incidence is not known. We conducted a retrospective study to identify patients with chemotherapy-induced permanent alopecia after HSCT. We describe six such patients, two males and four females, among 760 patients transplanted between 1997 and 2004. Median age was 45 years (range, 37-65). There were three Caucasians and three African-Americans. Median follow-up was 30 months. Conditioning regimens included BuCy, Bu/Cy and etoposide (VP16) (one of these patients received second autograft after Cy and TBI) and CyVP16 and TBI. Our data show that permanent alopecia is a significant long-term side effect of HSCT and can be seen across the spectrum of diseases and transplant types and with non-busulfan containing regimens. We have observed that patients usually accept permanent alopecia as the price for the cure and therefore true incidence of permanent alopecia may be underestimated. Our findings may also have medico legal and psychosocial implications that need to be taken into consideration when consenting patients for HSCT.

Poor mobilization of peripheral blood stem cells is a risk factor for worse outcome in lymphoma patients undergoing autologous stem cell transplantation.

The effect of poor blood stem cells mobilization on the outcome of autologous stem cell transplantation (ASCT) has not been well studied. Our aim is to evaluate poor mobilization as a prognostic factor in lymphoma patients undergoing ASCT. We analyzed 90 consecutive patients with Hodgkin's (HD) and non-Hodgkin's lymphoma (NHL) who underwent ASCT. Poor mobilization was defined as the inability to obtain > or = 1 x 10(6) CD34+ cells/kg ideal body weight with two large volume aphereses. Patients were divided into 2 groups: group 1 = poor mobilizers, and group 2 = good mobilizers. The poor mobilizers received lower median transplant CD34+ cell dose (2 x 10(6) vs. 4.5 x 10(6)/kg for good mobilizers, P = 0.001), were more heavily pretreated (P = 0.01), and required higher number of aphereses for PBSC collection (P = 0.0006). The median progression-free survival (PFS) in groups 1 and 2 was 10 and 41 months (P = 0.04), while the median overall survival (OS) was 38 months and not reached (P = 0.02), respectively. Univariate analysis showed that > or = 3 pre-transplant treatments, CD34+ cell dose < or = 2 x 10(6), elevated LDH before transplant, and poor mobilization were significant prognostic factors for poor PFS, while only the first three were significant for worse OS. Multivariate analysis using these same four factors revealed that number of pre-transplant treatments (HR = 6.03, P = 0.001), CD34+ cell dose (HR = 0.1, P = 0.0007) were the only independent predictive factors for worse overall outcome. In conclusion, our data show that poor mobilization could indicate poor outcome in lymphoma patients undergoing ASCT, however, it is more likely to be a reflection of the heavy pre-transplant therapy and lower CD34+ cell dose re-infused in this group of patients.

Correlation of early lymphocyte recovery and progression-free survival after autologous stem-cell transplant in patients with Hodgkin's and non-Hodgkin's Lymphoma.

The importance of the association between early lymphocyte recovery and outcome has not been well studied in autologous stem cell transplantation (ASCT). In this retrospective study, we analyzed 90 consecutive patients with non-Hodgkin's and Hodgkin's lymphoma who underwent ASCT. Patients were divided into two groups: group 1 with absolute lymphocyte count (ALC) on day +15 below the median of 667/mm(3), and group 2 with ALC >or=667/mm(3). The median progression-free survival (PFS), but not overall survival (OS), was significantly longer in group 2 when compared to group 1 (16 months vs not reached P=0.02). Group 2 patients also had significantly shorter hospital stay, received higher CD34(+) cell dose, and had shorter time to neutrophil recovery. Multivariate analysis demonstrated day +15 ALC to be an independent prognostic indicator for PFS, but not OS, while CD34(+) cell dose and the number of pretransplant treatments were better predictors for both PFS and OS. We conclude that higher day +15 ALC may independently predict better PFS after ASCT for lymphoma patients; however, whether this merely reflects faster overall recovery caused by higher infused CD34(+) cell dose and less pretransplant therapy needs further investigation.

Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital.

Despite new antifungal treatment strategies, invasive aspergillosis (IA) remains a principal cause of infectious mortality after bone marrow transplantation (BMT). We reviewed the medical records of 93 allogeneic and 149 autologous transplant recipients during a 20 month period, with attention to cases of proven or probable IA. No autologous transplant recipient developed IA, whereas IA was seen in 15.1% of allogeneic recipients (including two of five patients with a prior history of IA despite prophylaxis), for an overall incidence of 5.8%. The median time to occurrence was 92 days post transplant, with no de novo cases developing prior to engraftment. Survival 100 days from diagnosis was 29%. Risk factors for the development of IA included > or = 21 days of corticosteroid therapy of >or= 1mg/kg/day and post-transplant cytomegalovirus (CMV) infection. These two risk factors were statistically linked. Our data illustrate a shift toward a later occurrence of post-transplant IA, suggesting a need for close, prolonged surveillance in the outpatient environment. The contributory role of protracted corticosteroid use is also highlighted. These data have important implications in an era of alternate donor transplants and more intense immunosuppression. Established strategies implementing newer, less toxic antifungal agents as prophylaxis in high-risk patients are needed.

Engraftment syndrome in breast cancer patients after stem cell transplantation is associated with poor long-term survival.

An autoaggression graft-versus-host (GVHD)-like syndrome or engraftment syndrome (ES) presenting with skin rash, fever, and other clinical findings can accompany the early phase of engraftment after autologous peripheral blood stem cell (PBSC)/bone marrow (BM) transplantation. Because ES was suggested to be analogous to GVHD, we have investigated whether ES was associated with any graft-versus-tumor effect that would affect disease progression and survival in breast cancer patients. Eighty-five consecutive patients who received BM/PBSC transplantation for breast cancer (stages II-IV) between July 1991 and July 1997 with minimum 2-year follow-up were studied. Median follow-up time was 892 days (range, 106-2913 days). Thirty-three patients (39%) developed ES. The incidence of relapse/progressive disease for the whole cohort was 61% and was similar in patients who developed ES compared with those who did not. However, there was an increased rate of mortality observed among the patients who had developed ES versus those who had not, although it was statistically not significant, (52% versus 31%, respectively; log rank, P = .08). Increased mortality rates due to disease progression were seen in all patients with ES regardless of their disease stage. In relapsed patients, median survival time after transplantation was 586 days for those with ES versus 847 days for those without ES, and the mortality rate was 85% (17/20) versus 51% (16/31) (P = .008) for those with or without ES, respectively. Visceral (lung, liver, brain, adrenal) or multiple-site relapses were observed in 85% of patients with ES versus 52% without ES (P = .01). In conclusion, whereas there was no effect of ES on relapse rate, a surprisingly significant increase in disease-related mortality rates among relapsed breast cancer patients with ES was found. Thus, patients with ES should be considered for close follow-up and further therapy posttransplantation.

Gastroparesis following bone marrow transplantation.

Patients often develop nausea, vomiting and bloating after bone marrow transplantation (BMT). These symptoms may interfere with nutrition and the ability to take oral medications. Gastroparesis is a recognized cause of these symptoms in non-transplant patients but less is known about patients who undergo BMT. Between January 1996 and March 1997, a total of 151 patients underwent BMT. Eighteen patients (12%) developed persistent symptoms suggestive of gastroparesis (persistent nausea, vomiting or bloating). Scintigraphic gastric emptying studies were performed to assess for gastroparesis. Prokinetic agents were administered at the time of study. The records on these patients were compared with those of all other patients undergoing BMT during the same time period without these symptoms. Nine patients who demonstrated delayed gastric emptying were further evaluated with esophagastroduodenoscopy and biopsy. Biopsy samples were reviewed for evidence of graft-versus-host disease (GVHD). Fourteen of 18 patients demonstrated delayed gastric emptying and most responded to prokinetic agents given at the time of study. Age, conditioning regimen, cytomegalovirus antigenemia and acute GVHD did not appear to be associated with the development of gastroparesis. Allogeneic BMT recipients were at higher risk than autologous BMT patients (26% vs 0%, P < 0.0001). of allogeneic bmt recipients, there was a nonsignificant trend of patients receiving tacrolimus to be less likely to experience gastroparesis than those receiving cyclosporine (27% vs 48%, P = 0.08). For the nine patients undergoing upper endoscopy, GVHD on gastric biopsy was an uncommon finding and was mild when present. Gastroparesis appears to be a common cause of nausea, vomiting and bloating following allogeneic BMT. This may occur less often with tacrolimus than cyclosporine because of the former agent's prokinetic properties. Patients usually respond to prokinetic drugs at the time of scintigraphy. GVHD and CMV infection do not appear to be major contributing factors.

Expression of antisense RNA to aldehyde dehydrogenase class-1 sensitizes tumor cells to 4-hydroperoxycyclophosphamide in vitro.

Previous studies in this laboratory showed that the overexpression of human aldehyde dehydrogenase class-1 (ALDH-1) with a retroviral vector resulted in increased resistance to 4-hydroperoxycyclophosphamide (4-HC), an active metabolite of cyclophosphamide. The present study examined the effect of ALDH-1 antisense RNA expression on ALDH-1 activity and sensitivity to 4-HC toxicity. Three different ALDH-1 cDNAs were synthesized that are either missing the N terminus (N), C terminus (C), or both (NC) and subcloned into the BamHI cloning site of pLXSN retroviral vector in the antisense (AS) orientation (AS-N, AS-C, and AS-NC, respectively). It was demonstrated that the overexpression of each of the AS constructs in K562 leukemic cells and A549 lung cancer cells results in suppression of ALDH-1 mRNA and enzymatic activity. Furthermore, the AS-N and AS-NC were generally more effective than AS-C in reducing the ALDH-1 activity. Both K562 and A549 cells expressing the ALDH-1 AS became significantly more sensitive to 4-HC toxicity as demonstrated by clonogenic and liquid culture assays. The increase in 4-HC sensitivity was in correlation with the degree of suppression of ALDH-1 activity. Moreover, such increase in 4-HC sensitivity, especially with AS-N and AS-NC, was to a similar degree seen with the use of diethylaminobenzaldehyde, a specific inhibitor of ALDH-1. These results indicate that ALDH-1 expression and activity can be specifically and effectively suppressed by AS RNA and lead to increased sensitivity to 4-HC.

Characterization and outcome of "hard to mobilize"' lymphoma patients undergoing autologous stem cell transplantation.

A "hard to mobilize" patient was defined as one in whom >or= 1x10(6) CD 34+ cells/kg cannot be obtained after two consecutive large volume aphereses. Forty-four consecutive Hodgkin's and non-Hodgkin's lymphoma patients who underwent autologous peripheral blood stem cell (PBSC) transplant treatment between June 1996 and June 1998 were included in this study. Twenty-one patients (48%) met the definition of "hard to mobilize" (Group I). All the rest of the patients (n=23) were the good mobilizers (Group II). The initial mobilization protocol for most patients was 10 microg/kg of G-CSF alone for both groups. For Group I, 7/21 (33%) patients were unable to achieve a minimal dose of >or= 1x10(6) CD34+ cells/kg even after a second mobilization attempt and/or bone marrow (BM) harvest (n=5). Overall, 11/21 (52%) required an additional mobilization and/or BM harvest. Only 3/21 (14%) patients were able to meet the target cell dose of >or= 2.5x10(6) CD34+ cells/kg (median of 4 apheresis). In contrast, 87% of Group II achieved the target dose with a median of 2 aphereses. Predictors of poor mobilization were greater than two prior treatment regimens (p=0.038) and the WBC count (<25,000/microL) on the first day of apheresis (p=0.053). Nineteen patients in Group I and all Group II completed treatment with a median time to engraftment of ANC>500/microl of 12 and 11 days, and platelet >20x10(3)/microl of 31 and 13 days, respectively. Outcome analysis revealed that 6/19 patients in Group I died of relapse within one year from transplant compared with only 2/23 of Group II who died of relapse (p=0.005, log rank test). There were no treatment related deaths in either group. Independent predictive features for "hard to mobilize" patients are a lack of significant increase in WBC count on the first day of apheresis and the number of prior treatment regimens. Poor mobilization appears to predict a worse outcome after autografting for lymphoma patients.

Comparison of autologous peripheral blood stem cell dosing by ideal vs actual body weight.

In this retrospective study, we evaluated the predictability of PBSC dose for hematopoietic engraftment comparing that calculated by ideal body weight (IBW) vs another calculated by actual body weight (ABW) for each patient. Sixty-three consecutive patients treated similarly using one transplant protocol were analyzed. While all patients had data available on CFU-GM and nucleated cells (NC), data on CD34+ enumeration was present only in 34 patients. We found that 49% of the patients were greater than 25% over their IBW. In addition, least-squares linear regression was used to assess the strength of the linear relationship between the inverse of cell dose/kg of ABW or IBW and time to AGC or platelet engraftment and showed no difference in r2 values for platelet engraftment, while using dose/kg of IBW greatly improved the ability of NC (r2 improved from 0.19 for ABW to 0.35 for IBW) and CFU-GM (r2 improved from 0.35 for ABW to 0.53 for IBW) to predict time to AGC engraftment, but did not change the CD34 r2. Hazard ratios were estimated using Cox proportional hazards regression and in all instances were found greater than 1.0 indicating that the probability of engraftment increased as cell dose/kg ABW or IBW increased. Finally, our data showed that 10 patients (16%) could have had one less apheresis procedure performed to obtain their set target stem cell dose calculated per kg IBW rather than ABW. In conclusion, PBSC dose per kg IBW is as good or better predictor of engraftment of AGC and may lead to cost savings in a certain subset of patients.

The effect of overnight storage of leukapheresis stem cell products on cell viability, recovery, and cost.

The cost of harvesting, processing, and freezing multiple peripheral blood stem cell (PBSC) products could easily exceed that of bone marrow harvest. To reduce costs while maintaining product viability, we examined the effect of overnight storage on PBSC products. Sixteen consecutive leukapheresis samples from 12 patients were examined prospectively. Each initial leukapheresis product was stored overnight on ice (median temperature 15 degrees C) after adding an equal amount of M199 culture medium containing heparin. After overnight storage, the product was combined with the next day PBSC harvest if required and processed/frozen per protocols. Parameters measured before and after storage include cell count and differential, viability, bacterial cultures, and colony-forming unit (CFU) assays. The results show that the median cell concentration during storage was 7.12 x 10(7)/ml and the median length of storage was 20 h. After storage, the median viability and nucleated cell recovery were 100% and 99.5%, respectively. In addition, 98% recovery of CFU-GM was achieved. No clotting or bacterial contamination was detected. All 12 patients studied engrafted promptly. In addition, 124 similarly treated patients were retrospectively analyzed. Of these, 48% required > or = 2 large-volume leukaphereses to achieve the target cell dose. As a result of overnight storage, 150 final products, instead of 224, were processed and cryopreserved. This difference is equivalent to 33% cost savings. Again, all patients were transplanted and engrafted successfully. In conclusion, overnight storage and pooling of two consecutive PBSC products are safe, reduce cost, and allow for optimum laboratory staffing.

Successful salvage using mismatched umbilical cord blood transplant in an adult with recurrent acute myelogenous leukemia failing autologous peripheral blood progenitor cell transplant: a case history and review.

We report a 26-year-old female with AML, FAB classification M5 who was initially treated with induction therapy consisting of idarubicin and cytarabine followed by high-dose cytarabine and autologous peripheral blood progenitor cell (PBPC) transplant for consolidation. The patient remained in remission for 1 month post-PBPC transplant, when relapse was noted. Reinduction therapy with idarubicin, cytarabine and etoposide was unsuccessful, and the patient underwent an unrelated, two-antigen mismatched umbilical cord blood (UCB) transplant for salvage after melphalan plus total body irradiation. Complications post transplant included veno-occlusive disease, delayed engraftment, and acute grade III graft-versus-host disease (GVHD). The patient remains in remission 1 year post transplant. This study demonstrates the salvage capability of UCB transplantation for refractory leukemia and its potential use in adult patients.

In vitro selection for K562 cells with higher retrovirally mediated copy number of aldehyde dehydrogenase class-1 and higher resistance to 4-hydroperoxycyclophosphamide.

Previously, we have reported the successful expression of human aldehyde dehydrogenase class-1 (ALDH-1) in K562 leukemia cells using a retroviral vector and demonstrated low expression that resulted in up to three-fold increase in resistance to 4-hydroperoxycyclophosphamide (4-HC), an active derivative to cyclophosphamide. The purpose of this study was to investigate whether in vitro treatment with 4-HC will allow selection of K562 cells expressing higher levels of ALDH-1, and whether these selected cells are more resistant to 4-HC. Stably transfected or transduced K562 cells with retroviral pLXSN vector containing ALDH-1 cDNA (ALDH-1 cells) were treated repeatedly with 4-HC and then allowed to grow to confluence in liquid culture. Subsequently, the resistance to 4-HC of ALDH-1 cells treated once (ALDH-1+) or twice (ALDH-1++) with 4-HC was compared to ALDH-1 cells or wild-type K562 cells (WT cells). The results show significant increase in 4-HC resistance of ALDH-1+ (2- to 16-fold, p < 0.005) over ALDH-1 or WT cells. No difference was detected between ALDH-1+ and ALDH-1++. In addition, higher ALDH-1 mRNA and enzyme activity were found in ALDH-1+ compared to ALDH-1 cells. Southern analysis of DNA extracted from the different experimental groups demonstrated an eight-fold increase in ALDH-1 cDNA in ALDH-1+ versus the ALDH-1 cells. This was confirmed by sequential FISH analysis using biotin labeled pLXSN/ALDH-1 vector. Positive signals consistently localized to the centromeric region of chromosome 9 and the long arm of chromosome 17 were demonstrated only in the ALDH-1+ cells and represented a fusion product of multiple copies of the pLXSN/ALDH-1 vector. In summary, we have demonstrated that in vitro treatment with 4-HC results in the selection of K562 cells with multiple copies of ALDH-1 gene that are clustered in two main integration sites. These cells demonstrate significantly higher resistance to 4-HC when compared to previously untreated cells. Such successful in vitro selection could have significant implications for future cancer gene therapy protocols.

Protection of hematopoietic progenitors from ultraviolet C by interleukin-1 and tumor necrosis factor-alpha.

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can protect hematopoietic progenitors from the toxicity of 4-hydroperoxycyclophosphamide (4-HC) and gamma radiation. We hypothesize that IL-1 and TNF-alpha may be inducing a universal stress reaction in hematopoietic progenitors. In this study, we examined their protective effects against ultraviolet C (UVC) compared with that seen against 4-HC using colony formation assays and flow cytometric analysis. We demonstrated that 20 h preincubation with IL-1 or TNF-alpha or both protected normal hematopoietic colony-forming cells (CFCs) from UVC. Colony formation assays and flow cytometric analysis of the cells protected from either 4-HC or UVC revealed that similar proportions of hematopoietic progenitors are protected in the IL-1 and TNF-alpha group in comparison to control. Furthermore, at least 20 h of preincubation with the two cytokines was needed for optimal protection. The addition of 2 micrograms/ml cycloheximide, a protein synthesis inhibitor, during the 20 h preincubation completely abolished the protection observed for CFCs. In conclusion, IL-1 and TNF-alpha can protect normal hematopoietic progenitors from UVC as well as from 4-HC and gamma radiation, and, therefore, a global response to DNA damaging treatments induced by IL-1 and TNF-alpha needs to be further investigated.

Human A1, a Bcl-2-related gene, is induced in leukemic cells by cytokines as well as differentiating factors.

Based on previously published observations regarding the protective effects of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) against gamma radiation, alkylating agents and ultraviolet radiation, we hypothesized that the protection against such DNA damaging treatments can be the result of a 'stress'-like response induced by these cytokines and mediated by early response cellular gene(s). By applying the mRNA differential display to RNA obtained from A549 lung carcinoma cell line that was incubated with 50 ng/ml IL-1 for 0, 1, 2, and 6 h, we identified several cDNA fragments that correspond to genes regulated by IL-1. The full length cDNA for one fragment was obtained using 5'RACE, cloned, sequenced, and found to be homologous to human A1, a Bcl-2-related gene. In this study, we report that the expression of human A1 is either absent or present at low levels in leukemic cells, while it is expressed in human bone marrow cells and abundant in peripheral blood progenitors. It is induced by IL-1 and TNF alpha in A549 lung carcinoma, bone marrow, and certain leukemic cells. A1 is also induced in leukemic cells during granulocytic or macrophage but not erythroid differentiation. In conclusion, this is the first demonstration that A1 is inducible by cytokines in human bone marrow and certain tumor cells as well as myeloid differentiation in leukemic cells.

Increased frequency of autoaggression syndrome associated with autologous stem cell transplantation in breast cancer patients.

In our BMT Unit, we have observed a high frequency of skin rash associated with fever and other clinical findings during engraftment of autologous BM and/or PBSC. Thirty patients with breast cancer and 12 patients with Hodgkin's or non-Hodgkin's lymphoma, treated with the same regimen, were analyzed retrospectively or prospectively to characterize the clinical syndrome, its frequency, and its clinical course, as well as to define the factors affecting its incidence. In patients developing skin rash, the median and range for time to onset of skin rash and for time to increase in WBC after reinfusion of stem cells were identical (8 days, range 5-13) and did not differ significantly (P = 0.533). Twenty-three patients (55%) had skin rash, 18 patients had fever. Other, less frequent manifestations include platelet transfusion refractoriness (PTR), diarrhea, diffuse alveolar hemorrhage, and autoimmune thrombocytopenia or hemolytic anemia. A higher proportion of breast cancer patients developed the syndrome in comparison to lymphoma patients (67% vs 25%, P = 0.051). Acute GVHD grade I-II was established histologically in six patients with the syndrome. Comparison of the incidence of the syndrome by different variables using Fisher's exact test revealed significance for disease category (P = 0.02) and number of previous treatment regimens (P = 0.002) as predictive factors for developing the autoaggression syndrome. In other words, patients with breast cancer and those with only one previous treatment regimen were more likely to develop the syndrome. This study suggests that an autoaggression GVHD-like syndrome accompanies the early phase of autologous engraftment and that a higher frequency of the syndrome might be seen in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation.