Ian Nivison-Smith

Human Gastrointestinal Neoplasia-Associated Myofibroblasts Can Develop from Bone Marrow-Derived Cells Following Allogeneic Stem Cell Transplantation†‡

This study characterized the contribution of bone marrow‐derived cells to human neoplasia and the perineoplastic stroma. The Australasian Bone Marrow Transplant Recipient Registry was used to identify solid organ neoplasia that developed in female recipients of male allogeneic stem cell transplants. Eighteen suitable cases were identified including several skin cancers, two gastric cancers, and one rectal adenoma. Light microscopy, fluorescence and chromogenic in situ hybridization, and immunohistochemistry were performed to determine the nature and origin of the neoplastic and stromal cells. In contrast to recent reports, donor‐derived neoplastic cells were not detected. Bone marrow‐derived neoplasia‐associated myofibroblasts, however, were identified in the rectal adenoma and in a gastric cancer. Bone marrow‐derived cells can generate myofibroblasts in the setting of human gastrointestinal neoplasia. STEM CELLS 2009;27: 1463–1468

The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study

Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous subset of lymphomas with a poorer prognosis compared with B-cell lymphomas. We conducted a retrospective study of 82 patients who received high-dose therapy for PTCL (autologous SCT (ASCT) N=64; allogeneic SCT (Allo-SCT) N=18). With a median follow-up from ASCT of 37 months from transplant, 33 patients were alive; 20 died of progressive disease, 10 died from non-relapse mortality (NRM) with 1 unknown cause. Three-year overall survival (OS) and progression-free survival (PFS) were 53% (95% confidence interval (CI) 42, 67) and 50% (95% CI 39, 64), respectively. Factors significantly affecting OS and PFS on univariate analysis were histological subtype and chemotherapy sensitivity. In a multivariate analysis, the only factor with significant impact was chemotherapy sensitivity. After a median follow-up from Allo-SCT of 57 months, five patients were alive; five died of progressive disease and eight died from NRM. The 3-year OS and PFS were 39% (95% CI 22, 69) and 33% (95% CI 17, 64), respectively, and the 3-year relapse rate was 28% (95% CI 6, 50). These results demonstrate that high-dose chemotherapy with autologous stem cell rescue has a substantial role in the management of T-cell lymphoma. The use of full-intensity allogeneic transplantation is limited by high transplant-related mortality, and exploration of reduced intensity regimens is warranted.

A comparison of the pattern of interstitial pneumonitis following allogeneic bone marrow transplantation before and after the introduction of prophylactic ganciclovir therapy in 1989

A comparison was made of the pattern of interstitial pneumonitis (IP) following allogeneic bone marrow transplantation before and after the introduction of ganciclovir prophylaxis to minimize the risk of cytomegalovirus (CMV) disease in the St Vincent’s Hospital bone marrow transplant program in 1989. A total of 456 recipients of allogeneic transplants were included. 280 received no prophylactic ganciclovir while 176 received prophylactic ganciclovir. The overall incidence of interstitial pneumonitis dropped from 19.6 to 12.5% (P = 0.03) and this was primarily due to a reduction in the incidence of CMV-IP which fell from 12.9 to 1.7% (P < 0.0005). the incidence of idiopathic ip was not different between the two groups (6.3 vs 3.2%), nor was the incidence of Pneumocystis carinii pneumonia (2.9 and 0.6%). Prophylactic ganciclovir has thus had a significant impact in reducing both the overall incidence of IP and specifically cytomegalovirus IP in allogeneic marrow transplant recipients. The most common form of IP in patients given prophylactic ganciclovir is now idiopathic interstitial pneumonitis.

Haemorrhagic cystitis: incidence and risk factors in a transplant population using hyperhydration

Haemorrhagic cystitis (HC) is the syndrome of haematuria and symptoms of lower urinary tract irritability in the absence of bacterial infection. We report a low incidence of HC (18.2%) in 681 haemopoietic stem cell transplant patients, using a prophylactic regimen of hyperhydration and forced diuresis. The incidence of grade 3–4 disease is 3.4%. There was a marked difference in incidence between allogeneic and autologous transplant populations, 24.2% vs 3.5% (P < 0.0005). busulphan conditioning, acute gvhd, interstitial pneumonitis and use of methotrexate and cyclosporin immune suppression were associated with significantly increased incidence of hc in the allogeneic population. this may reflect the numerous factors that contribute to the greater immunosuppression and consequent increased risk for hc in allogeneic transplantation.

Outcomes of haematopoietic stem cell transplantation for inherited metabolic disorders: a report from the Australian and New Zealand Children's Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry.

We report a retrospective analysis of 53 haematopoietic stem cell transplants for inherited metabolic disorders performed at ANZCHOG transplant centres between 1992 and 2008. Indications for transplant included Hurler syndrome, ALD, and MLD. The majority of transplants utilized unrelated donor stem cells (66%) with 65% of those being unrelated cord blood. Conditioning therapy was largely myeloablative, with Bu plus another cytotoxic agent used in 89% of recipients. Primary graft failure was rare, occurring in three patients, all of whom remain long‐term survivors following the second transplant. The CI of grade II‐IV and grade III‐IV acute GVHD at day +100 was 39% and 14%, respectively. Chronic GVHD occurred in 17% of recipients. TRM was 12% at day +100 and 19% at one yr post‐transplant. OS at five yr was 78% for the cohort, 73% for patients with ALD and 83% for patients with Hurler syndrome. There was no statistically significant difference in overall survival between unrelated marrow and unrelated cord blood donor groups. The development of interstitial pneumonitis was an independent variable shown to significantly impact on TRM and OS. In summary, we report a large cohort of patients with inherited metabolic disorders with excellent survival post‐allogeneic transplant.

Relative Survival of Long-Term Hematopoietic Cell Transplant Recipients Approaches General Population Rates

Whether the annual mortality rates of long-term hematopoietic cell transplant (HCT) survivors ever return to that of the general population is unclear. This study sought to determine the annual long-term mortality rates of allogeneic and autologous HCT recipients who had survived 5 years or more disease-free posttransplant and calculate their relative survival rates. Patients were included if they had a first allogeneic or syngeneic HCT for acute leukemia, chronic myelogenous leukemia (CML) or myelodysplastic syndromes (MDS), or autologous HCT for acute myelogenous leukemia (AML) or lymphoma in Australia or New Zealand between 1992 and 2001, recorded on the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) database, and were known to have survived, disease free, 5 years or more posttransplant. The annual mortality rates of 5-year transplant survivors were compared to standard Australian and New Zealand populations using relative survival. A total of 1461 HCT survivors (688 postallograft, 773 postautograft) were included in this study. The 10-year survival probability for 5-year allograft survivors was slightly higher than that of 5-year autologous survivors (93.4% versus 89.6%, P=.06). The relative survival of both allogeneic and autologous 5-year survivors was never <97% of that of the general population. However, it was statistically significantly lower than expected in the sixth to ninth years posttransplant, with no obvious pattern of either improvement or deterioration from 6 to 10 years posttransplant. This study indicates that annual relative survival rates of long-term survivors of allogeneic HCT performed in Australia and New Zealand for acute lymophoblastic leukemkia (ALL), AML, CML, and MDS are slightly, but significantly lower than population rates in the 6th to 10th years posttransplant. Annual relative survival rates of long-term survivors of autologous HCT performed in Australia and New Zealand for AML and lymphomas are also slightly lower than population rates up to the 10th year posttransplant. Late deaths from transplant and disease-related causes are unusual, but continue to occur for many years post-HCT.

Haemopoietic stem cell transplantation in Australia and New Zealand, 1992–2001: progress report from the Australasian Bone Marrow Transplant Recipient Registry

Background:  Bone marrow and blood stem cell transplantation is now used as curative therapy for a range of haematological malignancies and other conditions. The Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) has recorded transplant activity in Australia since 1992; transplant centres in New Zealand have corresponded with the Registry since 1998.

Second cancer risk in adults receiving autologous haematopoietic SCT for cancer: a population-based cohort study

Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992–2007 (n=7765). Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2–1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR=20.6), melanoma (SIR=2.6) and non-Hodgkin lymphoma (SIR=3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (>45 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors.

Post-transplant lymphoproliferative disease in heart and lung transplantation: Defining risk and prognostic factors

BACKGROUND Heart and lung transplant recipients have among of the highest incidence rates of post-transplant lymphoproliferative disease (PTLD). Despite this, there is a paucity of data specific to this group. We collated data on heart, lung and heart-lung transplant recipients with PTLD to identify disease features and prognostic factors unique to this group of patients. METHODS Seventy cases of PTLD were identified from a single institution (41 heart, 22 lung, 6 heart-lung and 1 heart-kidney transplant) from 1984 to 2013. Demographics, immunosuppression, treatment, response, complications and survival data were analyzed. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors. RESULTS The incidence of PTLD was 7.59% in heart-lung, 5.37% in heart and 3.1% in lung transplant recipients. Extranodal disease (82%) with diffuse large B-cell lymphoma (72%) was the most common presentation. Bone marrow involvement (13%) and central nervous system disease (3%) were uncommon. Heart transplant recipients had later onset of PTLD (>1 year post-transplant), with less allograft involvement, compared with lung and heart-lung recipients. Poor prognostic markers were bone marrow involvement (HR 6.75, p < 0.001) and serum albumin <30 g/liter (HR 3.18, p = 0.006). Improved survival was seen with a complete response within 3 months of treatment (HR 0.08, p < 0.001). Five-year overall survival was 29%. CONCLUSION This analysis is the largest to date on PTLD in heart and lung transplant recipients. It provides a detailed analysis of the disease in this group of patients and identifies unique prognostic features to aid risk stratification and guide treatment allocation.

Reduced intensity conditioned allograft yields favorable survival for older adults with B-cell acute lymphoblastic leukemia

Older adults with B‐cell acute lymphoblastic leukemia (B‐ALL) have poor survival. We examined the effectiveness of reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) in adults with B‐ALL age 55 years and older and explored prognostic factors associated with long‐term outcomes. Using CIBMTR registry data, we evaluated 273 patients (median age 61, range 55–72) with B‐ALL with disease status in CR1 (71%), >CR2 (17%) and Primary Induction Failure (PIF)/Relapse (11%), who underwent RIC HCT between 2001 and 2012 using mostly unrelated donor (59%) or HLA‐matched sibling (32%). Among patients with available cytogenetic data, the Philadelphia chromosome (Ph+) was present in 50%. The 3‐year cumulative incidences of nonrelapse mortality (NRM) and relapse were 25% (95% confidence intervals (CI): 20–31%) and 47% (95% CI: 41–53%), respectively. Three‐year overall survival (OS) was 38% (95% CI: 33–44%). Relapse remained the leading cause of death accounting for 49% of all deaths. In univariate analysis, 3 year risk of NRM was significantly higher with reduced Karnofsky performance status (KPS <90: 34% (95% CI: 25–43%) versus KPS ≥90 (18%; 95% CI: 12–24%, P = 0.006). Mortality was increased in older adults (66+ vs. 55–60: Relative Risk [RR] 1.51 95% CI: 1.00–2.29, P = 0.05) and those with advanced disease (RR 2.13; 95% CI: 1.36–3.34, P = 0.001). Survival of patients in CR1 yields 45% (95% CI: 38–52%) at 3 years and no relapse occurred after 2 years. We report promising OS and acceptable NRM using RIC HCT in older patients with B‐ALL. Disease status in CR1 and good performance status are associated with improved outcomes. Am. J. Hematol. 92:42–49, 2017.