Fatal Veno-occlusive Disease Research Articles

COMPARABLE OUTCOMES AFTER BUSULFAN- OR TREOSULFAN-BASED CONDITIONING FOR ALLO-HSCT IN CHILDREN WITH ALL – RESULTS OF FORUM

The superiority of TBI-based versus chemotherapy-conditioning for allo-HSCT in children with ALL has been established in the international, prospective phase-III FORUM study (#NCT01949129), randomizing 417 patients ≤ 18 years at diagnosis (4-21 years at HSCT) in CR, transplanted from HLA-matched sibling or unrelated donors. Due to the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the pre-specified comparison of outcomes of patients receiving busulfan-based (BU) or treosulfan-based (TREO) regimens from 2013 to 2018. 180 and 128 patients (median age 9.9 years) received BU/THIO/FLU or TREO/THIO/FLU, respectively. Data were analysed as of 02/2023, with a median follow-up of 4.2 years (range 0.3-9.1). Three-year overall survival was 0.71 (0.64-0.77) (BU/THIO/FLU) and 0.72 (0.63-0.79) (TREO/THIO/FLU), event-free survival was 0.60 (0.53-0.67) (BU/THIO/FLU) and 0.55 (0.46-0.63) (TREO/THIO/FLU), with both p = NS. The 3-year cumulative incidence of relapse (0.31 (0.25-0.38) BU, 0.36 (0.27-0.44) TREO, p = 0.779) and non-relapse mortality (0.08 (0.05-0.13) BU, 0.09 (0.05-0.15) TREO, p = 0.831) were comparable (p = NS). One case of fatal veno-occlusive disease occurred in each group. No significant differences in acute and chronic GvHD or GvHD-free and relapse-free survival (0.48 (0.41-0.55) BU, 0.45 (0.37-0.54) TREO, p = 0.89) were recorded. Outcomes for CR1 or CR2 patients were similar irrespective of the regimen used. In conclusion, BU/THIO/FLU or TREO/THIO/FLU regimens can be an alternative to TBI for ALL patients > 4 years with contraindications or lack of access to TBI.

Refractory Thrombocytopenia Is a Valid Early Diagnostic Criteria for Hepatic Veno-Occlusive Disease in Children.

We compared the incidence of refractory thrombocytopenia (RT) and platelet transfusion requirements (PTR) in 35 children who developed veno-occlusive disease (VOD) with 35 matched control subjects who underwent hematopoietic stem cell transplant but did not develop VOD. RT developed in 100% of the VOD patients, at a median of 8 days before VOD diagnosis, as compared with 71.5% of the control group. VOD patients required more platelet transfusions than control subjects (median PTR, 6.9 mL/kg [range, .57 to 17.59] versus 3.57 mL/kg [range, 0 to 14.63], respectively) with a statistically significant difference (P < .0001). The number of days with platelet requirements was significantly higher for VOD patients as compared with control subjects (median 68% versus 39%, P =< .0001). The PTR peaked at ~12 mL/kg/day, 2 days before VOD diagnosis, whereas the PTR in the control population was 5 mL/kg/day. The positive predictive value of developing VOD was 88.9% (95% confidence interval, 66.5% to 97%) in patients who were given >7 mL/kg/day of platelets during the at-risk period of days +3 to +13 after transplant. For patients who received >8 mL/kg/day of platelets, the positive predictive value of developing VOD was 86.7% (95% confidence interval, 61.2% to 96.4%). There was no difference in the PTR in patients with mild to moderate VOD as compared with severe VOD; however, the PTR was higher in patients whose VOD did not resolve. The median daily PTR after the diagnosis of VOD in 17 patients who got defibrotide as compared with those who did not get defibrotide was 6.04 mL/kg and 5.72 mL/kg, respectively, but the difference was not statistically significant (P=.56). On univariate and multivariate analysis use of intravenous immunoglobulin was significantly associated with VOD (P=.0088) but was not significantly associated with fatal VOD. In conclusion, RT occurs in 100% of patients at a median of 8 days before VOD diagnosis. VOD should be suspected in any patient with RT after the exclusion of other causes of consumptive thrombocytopenia, especially if they require >7 mL/kg/day of platelets.

Factors associated with allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO) versus (v) conventional chemotherapy (C).

7007 Background: InO therapy in R/R ALL resulted in superior complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates v C in the Phase 3 INO-VATE trial (NCT01564784; Kantarjian NEJM 2016). More InO v C pts proceeded to HSCT (41% [45/109] v 11% [12/109]; P&lt;0.001). Factors associated with outcomes after HSCT are described. Methods: Full details have been published. Multivariate analyses (MVA) using Cox regression modeling were conducted to determine predictors of non-relapse mortality (NRM) and overall survival (OS). Results: As of 3/8/16, 108/326 pts underwent allogeneic HSCT (InO n=77; C n=31). Baseline characteristics were generally similar, except baseline platelet values were lower in InO v C pts. More InO v C pts achieved minimal residual disease negativity (MRDneg [best status]; 71% v 26%; P&lt;0.0001). Less InO v C pts received additional therapy before HSCT (14% v 55%, P&lt;0.0001). NRM rates were higher in InO v C pts at 1 year (yr; 36% [95% CI 26–47] v 20% [8–36]) and 2 yrs (39% [27–51] v 31% [13–51]), but relapse rates were lower (1 yr, 23% [15–33] v 29% [13–48]; 2 yrs, 33% [22–44] v 46% [24–65]). No significant difference in post-HSCT survival was detected in InO v C pts; however, visual inspection of the curve suggested the survival probability varied before and after 15 months post-HSCT (1 yr, 44% [95% CI 33–55] v 65% [44–79]; 2 yr, 39% [28–50] v 34% [15–54]). Fatal veno-occlusive disease (VOD) was observed in 5 InO pts (all during the first 100 days from the date of HSCT) and no C pts. MVA showed that conditioning regimens without dual alkylators and thiotepa were associated (2-sided; P&lt;0.05) with lower risk of NRM and post-HSCT survival, respectively. Conclusions: Compared with C, InO permitted more pts with R/R ALL to proceed to HSCT in CR/CRi with MRDneg (best status). Despite increased NRM and fatal VOD, long-term survival was attainable in InO pts. In pts previously treated with InO, interventions to reduce NRM and improve OS after HSCT include avoiding dual alkylator conditioning regimens, especially those containing thiotepa. Funding: Pfizer Clinical trial information: NCT01564784.

Hemophagocytic Syndrome Associated with Fatal Veno-Occlusive Disease in the Liver

A 47-year-old man presented with hemophagocytic syndrome (HPS) without any obvious underlying diseases. On computed tomography, his liver was occupied by multiple ill-defined low intensity lesions. Liver biopsy revealed diffuse infiltration of numerous histiocytes without cytologic atypism and prominent fibrotic changes. These histiocytes showed S100(+), CD68(+), CD1a(-), and lysozyme(+) and Langerhans cell granules were not observed by electron microscopic examination. He failed to respond to immunosuppressive and chemotherapeutic treatments and progressed to severe liver failure. At autopsy, his liver exhibited veno-occlusive disease (VOD). Since VOD is regarded as a rare complication of HPS, the presence of VOD associated with HPS may be easily overlooked.

Veno‐occlusive disease of the liver in a child after chemotherapy for brain tumor

Veno-occlusive disease (VOD) of the liver is a life-threatening state generally occurring as a complication of bone marrow transplantation or chemotherapy for Wilms' tumor. Veno-occlusive disease after standard dose chemotherapy in malignancies other than Wilms' tumor is rare and only a few cases have been published in children. We report a 19 month-old-girl with medulloblastoma who experienced fatal VOD of liver after only one course of chemotherapy including carboplatin, vincristine and CCNU for medulloblastoma. As our knowledge, this is the first report of VOD after standard dose chemotherapy for brain tumor in childhood.

Etoposide Containing Preparative Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia.

[Purpose] Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the powerful therapeutic tools for patients with adult lymphoblastic leukemia (ALL) even though transplant-related toxicity and the recurrence of leukemia are still problematic. In order to improve outcome of patients with adult ALL who received allo-HSCT, we investigated the clinical efficacy and safety of etoposide containing conditioning regimen for allo-HSCT.[Patients and Methods] Adult patients (including patients with 17, 18 and 19 years of age) with ALL were treated between February 1991 and October 2003 in our institute. When patients attained complete remission (CR) by induction therapies using JALSG ALL protocols or others, they received allo-HSCT [bone marrow (BMT), peripheral blood stem cell (PBSCT), and cord blood transplantation (CBT)]. Conditioning regimen was consisted with etoposide (60 mg/kg), cyclophosphamide (120 mg/kg), and fractionated total body irradiation (10 Gy) (CY/ETP/TBI). As clinically indicated, cytosine arabinoside (CY/ETP/TBI/AraC) or nimustine hydrochloride (CY/ETP/TBI/ACNU) was added to CY/ETP/TBI.[Results] In the 23 patients [male/female: 15/8, median age was 30 years (range 17–50 years)], 19 patients received BMT (13 from related and 6 from un-related donor), 3 received PBSCT from related donor, and one was performed CBT. As the conditioning regimen, 16 patients received CY/ETP/TBI, 4 received CY/ETP/TBI/AraC, and 3 received CY/ETP/TBI/ACNU. Six out of 23 patients had Philadelphia chromosome positive ALL. Twenty-two patients received HLA serologically identical donor. Remission status at transplant included 16 patients in 1st CR, 5 in 2nd CR, and other 2 patients in non-CR. Grade II toxicity according to Bearman scale was observed in 52% (stomatitis), 22% (gastrointestinal), 9% (bladder), 4% (hepatic), and 4% (cardiac). Critical regimen-related toxicities and fatal veno-occlusive disease were not observed in any patients. The disease-free (DFS) and over-all survival (OS) rate of all patients was 51.1 % and 55.8 %.[Discussion/Conclusion] These results indicated that an intensified etoposide containing preparative regimen is a feasible regimen and it has good efficacy for transplant recipients with ALL.

Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation.

Mylotarg (Wyeth-Ayerst Laboratories, St. Davids, PA) is the brand name for a calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab ozogamicin, CMA-676) and has been approved recently for the treatment of a subset of elderly patients who have relapsed acute myeloid leukemia (AML). Mylotarg is associated with an incidence of approximately 20% Grade 3 or 4 hyperbilirubinemia and liver transaminitis in this patient population. Hepatic venoocclusive disease (VOD) has been reported in patients who have undergone stem cell transplantation (SCT) after Mylotarg therapy. Outside of the SCT setting, VOD has been associated very rarely with cytotoxic therapy. The authors assessed the incidence of VOD in 119 patients who were receiving Mylotarg-containing non-SCT regimens. VOD was diagnosed through the use of standard Seattle and Baltimore criteria. A cohort of 119 (61 previously untreated, 58 with relapsed disease) patients with AML (92 patients), advanced myelodysplastic syndrome (25 patients), or chronic myeloid leukemia in blast phase (2 patients), received Mylotarg-based regimens. Fourteen (12%) developed VOD. The diagnosis of VOD was supported by histology in 2 patients and radiologic studies in a further 10 patients. Five (36%) of 14 patients with VOD had received no prior antileukemic cytotoxic therapy, including 2 patients who received single-agent Mylotarg therapy. Mylotarg was shown to be associated with the development of potentially fatal VOD in patients with leukemia who had not received SCT. VOD occurred when Mylotarg was used either as a single agent or when it was given with other cytotoxic agents. VOD occurred in Mylotarg-treated patients who had received no prior cytotoxic therapy. The current study concluded that risk factors for VOD should be assessed when considering Mylotarg therapy, and that attempts to avoid and treat VOD are warranted in patients who receive Mylotarg therapy.

THE PATHOLOGY, DIAGNOSIS, AND TREATMENT OF HEPATIC VENO‐OCCLUSIVE DISEASE: CURRENT STATUS AND NOVEL APPROACHES

THE PATHOLOGY, DIAGNOSIS, AND TREATMENT OF HEPATIC VENO‐OCCLUSIVE DISEASE: CURRENT STATUS AND NOVEL APPROACHES

Premarrow Transplant Evaluation for Risk of Critical Illness

Critical illness requiring support in an intensive care unit (ICU) is common after blood and marrow transplantation, occurring in > 20% in some series. Attempts have been made to identify patients at highest risk of respiratory, cardiac, hepatic, and renal failure before trans plantation. Whereas demographic features, such as age and presence of active malignancy, are strongly associated with complications after transplant, only a few specific laboratory studies are useful in identifying high-risk individuals. Pulmonary function testing is associated with fatal pulmonary complications, and hepatic function tests are associated with fatal veno-occlusive disease of the liver. Knowledge of the predictive value of specific risk factors is important to the evaluation of patients considered for transplant.

Liver dysfunction in allogeneic bone marrow transplantation recipients.

Liver dysfunction is common in allogeneic bone marrow graft recipients, but no systematic studies of pre- and posttransplantation liver biopsies have been performed to identify and compare hepatic lesions. This study involved 25 consecutive patients who had undergone serial viral screening tests, liver tests, and pre- and posttransplantation liver biopsy. The aims were to ascertain the origin of liver disorders prior to bone marrow transplantation, to determine the mechanism and severity of liver dysfunction occurring early after transplantation, and to identify a possible relationship between pre-existing liver lesions and the frequency and nature of early liver dysfunction after transplantation. Pretransplantation biochemical liver tests were abnormal in 72% of patients, despite the absence of clinical liver disease. Eleven patients had chronic viral hepatitis B or C. Mild or moderate histological lesions were present in all the patients, with bile duct abnormalities in 48%, central vein abnormalities in 24%, sinusoidal fibrosis in 52%, portal fibrosis in 88%, portal necrosis in 52%, and parenchymal siderosis in 76%. After transplantation, fatal veno-occlusive disease occurred in two patients and biochemical abnormalities occurred in 24. Coded review of needle biopsy specimens failed to provide a single diagnosis. Histological lesions differed between pre- and posttransplantation biopsy specimens only by increased iron overload (96%, P<0.01). We conclude that pretransplant liver lesions contribute to hepatic dysfunction early after bone marrow transplantation, being very similar in nature and degree to lesions observed posttransplantation.

DOES HIGH-DOSE INTRAVENOUS IMMUNE GLOBULIN TREATMENT AFTER BONE MARROW TRANSPLANTATION INCREASE MORTALITY IN VENO-OCCLUSIVE DISEASE OF THE LIVER?

Forty-five recipients of bone marrow from HLA-identical siblings were given intravenous immune globulin (IVIG) 0.5 g/kg once a week during the first 3 months after transplantation. Fifty-three consecutive previously transplanted HLA-identical siblings were included as controls. Only patients who were cytomegalovirus (CMV) seropositive or had a CMV-seropositive donor were included. There were no major differences in patient characteristics between the two groups. However, more patients in the IVIG group received individualized graft-versus-host disease (GVHD) prophylaxis with less cyclosporine (P < 0.01), more controls received liposomal amphotericin B (P = 0.01), and more patients in the IVIG group received low-dose heparin as prophylaxis against veno-occlusive disease of the liver (P < 0.001). Median follow-up was 21 months in the IVIG group and 47 months in the control group. There were no differences between the groups with regard to time to engraftment, hospitalization time, or days with fever. No differences between the IVIG group and control group were detected in the incidence of acute GVHD grade II-IV (17% vs. 23%) or chronic GVHD (30% vs. 42%). The incidence of bacterial septicemias (53% vs. 63%) and invasive fungal infections (9% vs. 6%) was unaffected by IVIG treatment. The incidence of symptomatic CMV infection was the same in the two groups (14% vs. 16%). One control patient died of CMV interstitial pneumonitis, and 1 patient from each group died from viral interstitial pneumonitis of other origin. The incidence of veno-occlusive disease (VOD) was 16% in the IVIG group versus 6% in the controls (P = NS). Fatal VOD occurred in 11% of the IVIG group compared with none of the controls (P = 0.02). Other transplant-related complications did not differ between the two groups. Two-year survival was 62% in the IVIG group and 60% in the controls (P = NS). No significant beneficial effect was seen with IVIG, which may increase mortality in VOD. The use of high dose IVIG as prophylaxis in marrow transplant recipients is questioned.

Azathioprine hepatotoxicity after liver transplantation

We report the first two cases of apparent azathioprine hepatotoxicity occurring after liver transplantation. The two patients exhibited jaundice, elevated serum transaminase activities and histopathological features of sinusoidal congestion and centrilobular hepatocellular degeneration 17 and 61 days after transplantation. After withdrawal of azathioprine, liver test results improved immediately in both patients. Recurrence of liver injury after another challenge with azathioprine was seen in the first case. Previously, fatal venoocclusive disease occurring after kidney transplantation had been attributed to azathioprine. Irreversible venoocclusive disease and the reversible hepatotoxicity described in this report (i.e., sinusoidal congestion with centrizonal necrosis) most likely represent different stages of hepatic endotheliitis caused by azathioprine. Thus early diagnosis of azathioprine hepatotoxicity is of great importance.

Fatal pulmonary venoocclusive disease secondary to a generalized venulopathy: A new syndrome presenting with facial swelling and pericardial tamponade

We describe a patient who developed fatal pulmonary artery hypertension secondary to diffuse venulitis. This otherwise healthy young woman first presented with generalized venulopathy, with chemosis, facial swelling, pleural effusions, and pericardial tamponade. The symptoms partially responded to steroid therapy, but over a 2-year course, a rapidly progressive and fatal venoocclusive disease developed. No other primary condition was diagnosed, and at autopsy, the patient had striking venulitis throughout, including the pulmonary bed. We believe that this is a unique case of pulmonary hypertension resulting from a generalized venulopathy.

Technical modifications in hyperfractionated total body irradiation for T-lymphocyte deplete bone marrow transplant

The Medical College of Wisconsin implemented a major bone marrow transplant (BMT) program in July 1985. The type of transplants to be focused on were allogeneic T-lymphocyte deplete. Total body irradiation (TBI) was initially patterned after the Memorial method. Patients received total body irradiation in a sitting position at a dose rate of 20–25 cGy/minute with 50% attenuation lung blocks used both anterior/posterior and posterior/anterior. Electron boosting was utilized for the ribs beneath the lung blocks. Occasionally, lower extremity boosting was required because of the sitting position. A dose of 14 Gy was chosen since T-lymphocyte deplete bone marrow transplant data suggest the need for higher total doses to consistently obtain engraftment. This dose was given in 3 equal daily fractions over 3 days following conditioning chemotherapy. Six of 11 patients treated in this manner developed lethal pulmonary events. In response to the pulmonary toxicity, partial lung shielding was increased to 60% attenuation. In the next 107 patients receiving this program of total body irradiation there was a reduced incidence of fatal pulmonary events (10 cases of fatal idiopathic interstitial pneumonitis and 12 cases of fatal pulmonary infections) after a median follow-up of 9 months. This was an obvious improvement over the initial group. A significant level of hepato-renal toxicity was also observed with 14 Gy total body irradiation when no liver or kidney blocking was used. Of the first 20 patients treated, three cases of fatal veno-occlusive disease resulted. Subsequently, a 10% attenuation right sided liver block was added. Five of 98 patients treated with this block have developed fatal hepatic dysfunction, (median follow-up of 7.2 months). This incidence is not statistically different from the initial group but favors the use of the liver block. Some renal toxicity was also detected with the earlier regimen, especially in pediatric patients. Partial kidney blocking has been implemented to minimize this toxicity. Our current dose rate has been reduced to 8 cGy/minute in a further attempt to reduce organ toxicity. To date, this selective blocking has not adversely affected the excellent rate (96%) of first time engraftments.

Pulmonary veno-occlusive disease in siblings: Case reports and morphometric study

Two cases of fatal veno-occlusive disease are described: the first in a boy 14 years old and the second in his sister, who died, at age 13, only a few months later. In both, the first symptom was effort-induced dyspnea and the course of the disease was rapid. The chest radiograph of the boy showed diffuse opacities, whereas that of the girl showed Kerley lines bilaterally. In both, at autopsy, a diagnosis of severe veno-occlusive disease was confirmed, with partial or complete occlusion of much of the pulmonary venous bed by organized thrombi. The pulmonary vascular system of the girl was processed for light microscopic morphometry by injection of radiopaque medium into the veins of one lung and the arteries of the other. Although there was little filling of the venous system, much of the arterial system filled down to the capillary level. Pre-acinar and intra-acinar arteries showed medial hypertrophy and extension of smooth muscle into precapillary arteries. The concentration of patent intra-acinar arteries relative to alveoli was not significantly less than normal, whereas the concentration of veins was strikingly reduced. Possible pathogenetic mechanisms are discussed.

Fatal veno-occlusive disease of the liver following high dose chemotherapy, irradiation and bone marrow transplantation

In two patients fatal veno-occlusive disease of the liver developed after bone marrow transplantation for underlying malignancies. Both had received significant pretransplant chemotherapy, including cystosine arabinoside, and total body irradiation. The diagnosis of veno-occlusive disease should be considered in patients in whom hepatomegaly, ascites and deteriorating liver function tests develop after they have received cancer chemotherapy.