Dasatinib-induced massive left chylothorax in a patient with chronic myeloid leukemia.

Dasatinib, an effective second-generation tyrosine kinase inhibitor, is used to treat breakpoint cluster region-Ableson-positive chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphocytic leukemia. One common adverse event associated with dasatinib use is fluid retention, including pleural effusion. Chylothorax, however, is a rare adverse event. Although the precise mechanism of dasatinib-induced chylothorax is unclear, almost all cases involve right or bilateral chylothorax, and mostly occur within 5 years of dasatinib initiation. Here, we report a rare case of a patient with dasatinib-induced massive left chylothorax 10 years after dasatinib initiation, which improved after dasatinib termination and a switch to bosutinib.

Feasibility of six cycles of lenalidomide-based triplet induction before stem cell collection for newly diagnosed transplant-eligible multiple myeloma.

OBJECTIVES: Achieving a deep response with induction therapy has a major impact on outcomes following autologous stem cell transplantation. Although longer and intensified induction therapy may provide better disease control, longer exposure to lenalidomide negatively affects stem cell yield. We examined the feasibility of 6 cycles of lenalidomide-based triplet induction therapy before stem cell collection in transplant-eligible multiple myeloma patients. METHODS: In this prospective study, patients received a combination of bortezomib, lenalidomide, and dexamethasone for 6 cycles. For patients who did not achieve a deep response after 3 cycles, bortezomib was substituted with carfilzomib for the last 2 cycles (5th and 6th courses). RESULTS: Although only half of the patients achieved a deep response after 3 cycles, all but 1 patient achieved a very good partial response (n = 4) or complete response (n = 5) after completing 6 cycles. Among 9 patients who received cyclophosphamide-based stem cell mobilization, 1 patient required a second mobilization that was successfully performed using plerixafor. After autologous transplantation, 7 patients showed complete response, including 5 with minimal residual disease-negative status. CONCLUSION: This study demonstrates that 6 cycles of lenalidomide-based induction therapy before stem cell collection are a feasible and promising approach for transplant-eligible newly diagnosed multiple myeloma patients.The study is registered at UMIN Clinical Trials Registry as UMIN000026936.Trial registration: UMIN Japan identifier: UMIN000026936.

Silicosis, then microscopic polyangiitis-antineutrophil cytoplasmic antibodies-associated vasculitis may be work-related disease in patients with silicosis.

A 74-year-old man with silicosis was admitted to the hospital because of prolonged fever. After referral to internal medicine for persistent fever and renal dysfunction, workup revealed antineutrophil cytoplasmic antibodies (ANCA) positivity. He was diagnosed with microscopic polyangiitis (MPA). After treatment with immunosuppressive therapy, his condition improved. Herein, we discuss silica exposure and the risk of ANCA-associated vasculitis (AAV), particularly in terms of work-related diseases. Silica exposure is a notorious risk factor for developing AAV, which is potentially lethal when not identified. When we see a silicosis patient with new-onset prolonged fever and generalized fatigue, AAV should be taken into consideration. This case report provides beneficial information to reliably assess patients at high risk of developing AAV in primary care settings.

Membranous nephropathy with acquired factor V inhibitor: a case report.

BACKGROUND: Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. In contrast, acquired factor V inhibitor is a rare bleeding disorder. CASE PRESENTATION: A 62-year-old Asian man with a history of cerebral hemorrhage, purpura, eosinophilia and hyper immunoglobulin E syndrome developed proteinuria. The bleeding disorder was diagnosed with acquired factor V inhibitors. A renal biopsy revealed that he suffered from membranous nephropathy with glomerular endothelial damage which is reported to be involved in another factor disorder. After the steroid administration, the coagulation test and proteinuria were improved. CONCLUSIONS: The presence of factor V inhibitors may have been involved in the development of membranous nephropathy.

Double-unit cord blood transplantation after myeloablative conditioning for patients with hematologic malignancies: a multicenter phase II study in Japan.

We analyzed the outcomes of 61 patients with hematologic malignancies who underwent double-unit cord blood transplantation (dCBT) after myeloablative conditioning performed as part of a prospective multicenter phase II study. The conditioning regimen for dCBT included total body irradiation, cyclophosphamide, and granulocyte colony-stimulating factor combined with cytosine arabinoside for myeloid malignancies and with total body irradiation and cyclophosphamide for lymphoid malignancies. The cumulative incidence of neutrophil engraftment after dCBT was 85% (95% confidence interval [CI], 73%-92%). All 51 of the patients who engrafted had complete chimerism derived from a single donor by day +60. Only the degree of HLA disparity in the host-versus-graft direction had an impact on unit dominance. The cumulative incidence of grade II-IV acute graft-versus-host disease was 25% (95% CI, 15%-37%), and that of chronic graft-versus-host disease was 32% (95% CI, 20%-44%). The 1-year cumulative incidence of relapse was 23% (95% CI, 13%-34%), and that of transplantation-related mortality was 28% (95% CI, 17%-39%). With a median follow-up of 41 months, event-free survival was 48% (90% CI, 37%-58%) at 1 year and 46% (90% CI, 35%-56%) at 3 years. Event-free survival at 3 years was 67% (95% CI, 46%-81%) for patients with standard risk and 29% (95% CI, 15%-45%) for those with advanced risk. This study suggests that dCBT after myeloablative conditioning is a promising alternative for adults and large children with hematologic malignancies who need stem cell transplantation but lack a suitable adult donor or an adequate single-unit cord blood graft.

Unrelated umbilical cord blood transplantation using a TBI/FLAG conditioning regimen for adults with hematologic malignancies.

A combined chemotherapy regimen comprising fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) has been used in the treatment of relapsed or refractory leukemias. We here report 38 patients with hematologic malignancies who underwent single-unit cord blood transplantation (CBT) with a conditioning regimen comprising 12-Gy total-body irradiation (TBI) and FLAG therapy (TBI/FLAG). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus or cyclosporin A and/or methotrexate. The median nucleated cell dose was 2.43 x 10(7)/kg (range: 1.96-3.55 x 10(7)/kg). Of 34 evaluable recipients, the cumulative incidence of donor engraftment was 97%. The median time to reach an absolute neutrophil count of 500/microL was 23 days (range: 18-35 days). The median time to an untransfused platelet count of 50,000/microL was 45.5 days (range: 28-208 days). Sixteen patients developed grades II-IV of acute GVHD. Fourteen patients were alive at a median follow-up of 46 months (range: 4-77 months). The estimated event-free survival at 3 years for all patients was 33.5%, with 72.7% in the standard-risk group (n = 11) and 17.7% in the high-risk group (n = 27) (P = .0075). These results showed that this novel regimen was well tolerated by patients and able to establish sustained donor cell engraftment, indicating the feasibility of TBI/FLAG as a conditioning regimen for CBT in adults with hematologic malignancies.

Familial adenomatous polyposis complicated by chronic myelogenous leukemia: response to imatinib mesylate.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyposis and a predisposition for developing colorectal cancer. FAP is frequently complicated by extracolonic disease, but complications of leukemia are rare. We present the first case of FAP complicated by chronic myelogenous leukemia (CML) in a 38-year-old man. The patient had numerous adenomas in the colorectum and a family history compatible with FAP. He was diagnosed as having FAP in February 2000. Two years after the diagnosis, he developed leukocytosis with the Philadelphia chromosome abnormality, indicating complication with CML. Imatinib mesylate was administered for the treatment of CML, and hematologic and cytogenetic remission of CML was achieved in 6 months. Numerous polyps, 2 to 3 mm in diameter, observed in the rectum prior to the administration of imatinib, regressed in size, but not in number, after 1 year of treatment with imatinib. Eighteen months later, however, the polyps were enlarged. In this patient, imatinib administration led to the remission of CML and might also have been responsible for the temporary regression of adenomatous polyps of FAP.

Serum elastase and antithrombin-3 levels after umbilical cord blood transplantation or bone marrow transplantation.

The severity of graft-versus-host disease (GVHD) was compared after cord blood transplantation (CBT) and bone marrow transplantation (BMT). The severity of GVHD was also analyzed in relation to serum elastase and antithrombin-3 (AT-3) levels. There was no significant difference in the average grade of acute GVHD between 49 BMT patients and 20 CBT patients (chi2-test). However, there was a lower incidence of patients without acute GVHD (grade 0) or patients with severe acute GVHD (grade 3 or 4) in CBT compared with BMT group. Linear regression analysis found no significant correlation between the serum elastase level and the grade of acute GVHD, between the serum AT-3 level and the grade of acute GVHD, or between the serum levels of elastase and AT-3 before conditioning and after engraftment. The AT-3 level after engraftment was significantly higher in the CBT group than in the BMT group and it did not fail along with the elevation of elastase in the CBT group (p < 0.01 by the Mann-Whitney U-test vs. the BMT group). In conclusion, the lower risk of severe acute GVHD in the CBT group may have been related to the smaller decrease of AT-3 after transplantation.

Changes of clotting factors (7, 9 and 10) and hepatocyte growth factor in patients with thrombotic microangiopathy after bone marrow transplantation.

To investigate risk factors for thrombotic microangiopathy (TMA) after bone marrow transplantation (BMT), the levels of three clotting factors (7, 9 and 10) and hepatocyte growth factor (HGF) were measured. Among 46 consecutive patients who underwent BMT, six developed TMA and 40 did not. The levels of the clotting factors and HGF did not differ significantly between the six patients with TMA and the 40 patients without it. In two patients who developed TMA during the earlyperiod after BMT, however, the levels of the three clotting factors were significantly decreased even before BMT, along with a significant increase of HGF. These findings suggest that patients with severe hepatic dysfunction before BMT, especially those with impaired protein synthesis, had an increased risk of developing TMA soon after BMT. It was also suggested that measurement of clotting factors (7, 9 and 10) and HGF may be useful to predict the occurrence of TMA in the early period after BMT.

Heparin cofactor II as a predictor of thrombotic microangiopathy after bone marrow transplantation.

The pathogenesis of thrombotic microangiopathy (TMA) after allogeneic bone marrow transplantation (BMT) remains unclear since ADAMTS13, which is implicated in primary thrombotic thrombocytopenic purpura (TTP), has been shown to have no role in this condition. We investigated whether the onset of TMA after BMT could be predicted by measuring heparin-cofactor II (HC II), a marker for thrombosis of unknown etiology. In 30 consecutive BMT patients, the serum HC II level was measured before conditioning and one week after recovery from leukopenia. Four of the 30 patients developed TMA, and 26 did not. Before conditioning, the mean serum HC II level was 1.748 +/- 0.37 U/mL in the TMA group and 0.889 +/- 0.25 U/mL, in the non-TMA group, being higher in the former group (p < 0.01, t-test). After recovery from leukopenia, the two groups showed no significant difference of serum HC II. The HC II level at the onset of TMA was above the upper limit of normal in only one out of four patients. These results suggest that vascular endothelial damage due to chemotherapy before BMT increases the risk of TMA, and that HC II is useful for predicting the occurrence of TMA after BMT.

Reduced-intensity conditioning followed by unrelated umbilical cord blood transplantation for advanced hematologic malignancies: rapid engraftment in bone marrow.

Reduced-intensity (RI) conditioning followed by cord blood transplantation (CBT) is a new treatment modality, but failure to engraft is a major concern. We describe 12 patients with advanced hematologic malignancies who underwent RI conditioning and CBT with a conditioning regimen consisting of 200 mg/m(2) fludarabine (Flu), 50 mg/kg cyclophosphamide (CY), and 3 Gy total body irradiation (TBI). Cyclosporin A and/or methotrexate were used for graft-versus-host disease prophylaxis. Cord blood grafts were not mismatched for more than 2 serologically defined HLA alleles but were later found by high-resolution DNA typing to be mismatched for 2 to 4 alleles in most cases. Short tandem repeat analysis of bone marrow cells at day 14 showed complete donor chimerism in 6 of the patients and mixed chimerism in 5, indicating rapid engraftment in the bone marrow, whereas the remaining patient experienced graft rejection. Neutrophil recovery was achieved at a median of day 17 (range, days 11-24) in 10 of the 11 patients with marrow chimerism at day 14. Of these 10 patients, however, transplantation-related mortality within 100 days occurred in 4 patients who showed failed platelet recovery and a lack of durable engraftment. Overall survival and disease-free survival rates were 41.7% and 33.3%, respectively. These results show that CB mismatched at 2 to 4 HLA alleles and transplanted with the Flu/CY/3 Gy TBI regimen is able to engraft in the bone marrow as early as day 14.

Prognosis value of atrial natriuretic peptide and brain natriuretic peptide for heart failure in patients undergoing allogeneic bone marrow transplantation.

It is essential to evaluate the organ function of the recipient before bone marrow transplantation (BMT). This study investigated the usefulness of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels as indicators of cardiac function. Seventy-five consecutive patients undergoing allogeneic BMT were enrolled. All of them had an ejection fraction of 55% or more on echocardiography. Six of the 75 patients died of heart failure after transplantation and these 6 patients were compared with the other 69 patients to assess the prognostic value of the two natriuretic peptides. Both peptides remained normal from before conditioning until recovery from leukopenia in all 69 surviving patients. Among the 6 patients who died of heart failure, however, BNP was increased in all 6 patients and ANP was increased in five of them at an average of 43.6 +/- 16.7 days before the onset of heart failure. Monitoring of these peptides may not only be useful for assessment of cardiac function but also for predicting the occurrence of heart failure.

Usefulness of sequential automated analysis of fragmented red blood cells for the differential diagnosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic hematopoietic cell transplantation.

Differentiating thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) from other complications following allogeneic hematopoietic cell transplantation (HPCT) requires objective, reliable markers. To this purpose, we assessed the clinical usefulness of sequential quantified analysis of fragmented red blood cells (FRC) with the Sysmex XE-2100 automated hematology analyzer. The correlation between manual and automated counting was significant (r = 0.917; P < .0001). Of 25 cases, the peak FRC percentage (FRC%) exceeded 1.3% after allogeneic HPCT in 11 cases, and lactate dehydrogenase levels were elevated in 5 of these 11 cases. Two patients received diagnoses of TTP-HUS following allogeneic HPCT, and both had initial diagnoses of acute graft-versus-host disease. In both cases, the sharp increase in the FRC% to >3% simultaneously with clinical exacerbation was helpful for differentiating TTP-HUS following allogeneic HPCT from other complications. We conclude that FRC% data sequentially obtained by an automated count seem to be useful as an objective marker of TTP-HUS following allogeneic HPCT.

Serum elastase and antithrombin-3 in patients with acute graft-vs.-host disease after bone marrow transplantation.

The mechanism by which inflammatory cytokines are involved in acute graft-vs.-host disease (GVHD) after hematopoietic stem cell transplantation has only been studied recently. We focused on the changes of serum elastase and antithrombin-3 (AT-3) from before pre-treatment until the leukocyte recovery period after transplantation. We examined the correlation between these two parameters and the grade of acute GVHD, as well as the mechanism of onset. We measured the serum elastase and AT-3 levels before pre-treatment and during the leukocyte recovery period in 49 consecutive patients receiving bone marrow transplantation. The severity of acute GVHD was divided into five grades (0-4). No significant differences of pre-transplantation elastase levels were observed among the GVHD grades, but the elastase level during the leukocyte recovery period showed a significant correlation with the grade of GVHD (p < 0.01). A significant inverse correlation was also observed (p < 0.05) between the pre-transplantation level of AT-3 and the grade of GVHD, as well as a significant correlation at the time of leukocyte recovery (p < 0.0001). Furthermore, a significant correlation (p < 0.0001) was observed between the elastase and AT-3 levels during the leukocyte recovery period. These results suggest that elastase levels during the leukocyte recovery period are related to the grade of acute GVHD and the mechanism appears to include vascular endothelial injury mediated via AT-3.

Heparin-induced thrombocytopenia antibody and the pathogenesis of thrombotic microangiopathy after stem cell transplantation.

Thrombotic microangiopathy (TMA) that occurs after stem cell transplantation (SCT) is generally regarded as being different from thrombotic thrombocytopenic purpura (TTP), because it is reportedly not associated with deficiency of von Willebrand factor-cleaving protease, whereas this enzyme is deficient in TTP. However, better understanding of the pathogenesis of this condition is still required. Accordingly, we investigated the relationship between TMA occurring after SCT and heparin-induced thrombocytopenia (HIT), a condition related to low-dosed heparin therapy that features thrombocytopenia and generalized thrombotic disorders. Thirty-nine consecutive patients who underwent bone marrow transplantation were divided into a TMA group and a non-microangiopathy group (10 and 29 patients, respectively). Before SCT, the serum platelet factor 4 (PF4) levels of the TMA and non-microangiopathy groups were 0.123 +/- 0.023 and 0.132 +/- 0.025, respectively (p = NS). One week after recovery of the white blood cell count following transplantation, the TMA group (0.2902 +/- 0.0678) had a significantly higher PF4 level than the non-microangiopathy group (0.1548 +/- 0.0312) (p < 0.001, t-test). Thus, PF4 increased after engraftment of the transplanted stem cells in the patients who developed TMA. In patients who developed TMA, there was a significant correlation between the PF4 level and the grade of angiopathy according to the Zeigler grading system (p < 0.01 by linear regression analysis). These results suggest that a HIT antibody produced by donor cells may be involved in the development of TMA after SCT.

Relationships between hematological recovery and overall survival in older adults undergoing allogeneic bone marrow transplantation.

OBJECTIVE: The advancement of hematopoietic stem cell transplantation techniques and the increase in frequency of hematological malignancy in older patients are expected to expand the indications to include more elderly patients. We investigated the problem of allogeneic bone marrow transplantation (allo-BMT) in patients over 40 years old. PATIENTS AND METHODS: We retrospectively analyzed 21 consecutive patients (13 males and 8 females) over 40 years old who underwent allo-BMT at our center during the past 12 years. RESULTS: The patients had a median age of 46 years, and 5 patients were over 50 years old. There were 8 cases of acute myelogenous leukemia (AML), 5 cases of acute lymphocytic leukemia (ALL), 6 cases of chronic myelogenous leukemia (CML) and 2 cases of myelodysplastic syndrome (MDS). The 3-year overall survival rate was 43.0%. Overall survival was associated with recovery of platelets in less than 30 days and recovery of neutrophil counts in less than 15 days. We did not observe any severe graft-versus-host disease (GVHD) or regimen-related toxicities. Twelve patients died of transplantation-related diseases. CONCLUSION: A faster recovery of the neutrophil and platelet counts was significantly associated with overall survival. Decreasing transplantation-related death, particularly by infection control, in allo-BMT in patients over age 40 is an important problem.

Association of Helicobacter pylori with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome after bone marrow transplantation.

Thrombotic microangiopathy (TMA) has attracted attention as a complication of bone marrow transplantation (BMT). The association of Helicobacter pylori (H. pylori) with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP/HUS) after BMT was studied. Among 74 consecutive patients undergoing transplantation, six developed TTP/HUS (the TTP/HUS group) and 68 did not (controls). These six patients were compared with the other 68 patients to investigate differences of the IL-12 and 8 levels, H. pylori and various clinical characteristics. The patients who developed TTP/HUS seemed not apparently different from those who did not in background characteristics, except that they had a significantly higher H. pylori-positive rate (p < 0.05). In the TTP/HUS group, however, the levels of interleukin-12 and interleukin-8 increased significantly during the leukocyte recovery after BMT and at the onset of TTP/HUS, respectively, to 45.8 +/- 57.6 pg/mL and 274.8 +/- 65.9 pg/mL (p < 0.05 for both), when compared with their levels of 5.0 pg/mL in the control group. Thus, H. pylori may play a role in the pathogenesis of TTP/HUS after BMT, with cytokines (interleukin-8 and interleukin-12) also being involved.

[New three-dimensional compensating filter for TBI using compu-former associated with RT LAN].

To shorten the TBI process, we developed a new device for making the three-dimensional (3D) compensating filter that improves dose distribution. The dose distributions in the phantom and manufacturing time were compared between the new device and the previous one. Clinical evaluations included dose distribution in patients and the clinical rate of interstitial pneumonitis (IP). Our 3D compensating filter is made of polystyrene resin and gypsum. The filter was made after performing two procedures as follows. Patient data were measured by CT, and the 3D dose-distribution data and 3D compensating-filter data were obtained from the CT data by the 3D radiation planning system. We were able to produce the new 3D compensating filter within about 4 hours, including all procedures. The average dose distribution to each site when the 3D compensating filter was used was 92.7% to the head, 102.1% to the thorax, 106.4% to the pelvis, 90.2% to the knee, and 93.8% to the ankle joint, when the scheduled dose was taken as 100%. Dose distribution was improved. IP occurred in 6 of 32 patients (18.8%). There was no significant difference between the TBI and non-TBI groups in the frequency of IP (p = 0.27).

Analysis of natural killer (NK) cell activity and adhesion molecules on NK cells from umbilical cord blood.

The activity of natural killer (NK) cells in human umbilical cord blood (CB) has been reported to be low, compared with that in adult peripheral blood (PB) in vitro. To examine the cause of this, after dividing the CD56+/CD3- cells in CB and PB into CD56bright and CD56dim NK cells, the NK cell activities and the expression of various surface antigens were assayed for each fraction. The NK cell activity of CD56dim NK cells in CB was significantly lower than that in PB (P = 0.0003), whereas, there was no significant difference between the NK cell activity of CD56bright NK cells in PB and CB. The expression levels of adhesion molecules (CD2, CD11a, CD18, DNAX accessory molecule-1), CD16, and CD57 for CD56dim NK cells in CB were significantly lower than those in PB, and approximately one-third of CB CD56dim NK cells were capable of forming conjugates with K562 cells, compared with PB CD56dim NK cells. Furthermore, the inhibition of both the NK cell activities and binding of CD56dim NK cells in PB and CB by monoclonal antibody against each of these adhesion molecules suggests that they play an important role in NK cell activity. These findings show that the low NK cell activity in CB is caused by the low NK cell activity of CD56dim NK cells and that the low expression level of adhesion molecules on CB CD56dim NK cells may contribute to this low NK cell activity.