Second cancers and late mortality in Australian children treated by allogeneic HSCT for haematological malignancy.

We examined risk of second cancer and late mortality in a population-based Australian cohort of 717 pediatric allogeneic stem cell transplant (HSCT) recipients treated for a malignant disease during 1982-2007. Record linkage with population-based death and cancer registries identified 17 second cancers at a median of 7.9 years post HSCT; thyroid cancer being the most common malignancy (n=8). The cumulative incidence of second cancer was 8.7% at follow-up, and second cancers occurred 20 times more often than in the general population (standardised incidence ratio 20.3, 95% confidence interval (CI)=12.6-32.7). Transplantation using radiation-based conditioning regimens was associated with increased second cancer risk. A total of 367 patients survived for at least 2 years post HSCT and of these 44 (12%) died at a median of 3.1 years after HSCT. Relapse was the most common cause of late mortality (n=32). The cumulative incidence of late mortality was 14.7%. The observed rate of late mortality was 36 times greater than in the matched general population (standardised mortality ratio 35.9, 95% CI=26.7-48.3). Recipients who relapsed or who had radiation-based conditioning regimens were at higher risk of late mortality. Second cancers and late mortality continue to be a risk for pediatric patients undergoing HSCT, and these results highlight the need for effective screening and survivorship programs.

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.

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients.

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

Volunteer unrelated donor experience after administration of filgrastim and apheresis for the collection of haemopoietic stem cells: the Australian perspective.

BACKGROUND: Voluntary donations of peripheral blood stem cells after administration of filgrastim (granulocyte-colony stimulating factor, G-CSF) are undertaken throughout the world by healthy individuals, but the short-, medium- and long-term adverse events during and after donation are not fully understood. AIMS: We document the experience of donors of peripheral blood stem cells mobilised by G-CSF at Australian Bone Marrow Donor Registry collection centres. METHODS: When the Australian Bone Marrow Donor Registry commenced collecting mobilised peripheral blood stem cells, based on data used for registration of G-CSF, all adverse reactions in donors were documented prospectively to determine the rate and severity of events. A total of 512 consecutive first-time donors assessed between July 2001 and March 2010 were included in this study. RESULTS: The median age at work-up was 40 years and 71% of donors were male. A large proportion of donors (91%) experienced bone pain during administration of G-CSF, and in fewer numbers headache (61%) and fatigue (61%). Bone pain was associated with a body mass index of overweight/obese (P = 0.03). Headache (P = 0.03), muscle pain (P = 0.03) and fatigue (P = 0.001) were all significantly associated with female sex. More than a quarter (28%) of donations involved a range of complications at collection. CONCLUSION: The incidence of short- and medium-term symptoms and events observed provide support for the information provided to unrelated donors at counselling. Follow up of the consequences of unrelated voluntary donation remains important to provide accurate and relevant information to prospective donors.

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.

Increased activity and improved outcome in unrelated donor haemopoietic cell transplants for acute myeloid leukaemia in Australia, 1992-2005.

BACKGROUND/AIM: Numbers of unrelated donor allogeneic haemopoietic cell transplants (HCT) for acute myeloid leukaemia have increased in Australia in recent years. The aims of this study were to investigate the components of this change and find contributing factors to changes in outcome. METHODS: The study method was a retrospective analysis of 213 consecutive first unrelated donor HCT for acute myeloid leukaemia performed within Australia for adult patients during the years of 1992-1997 (n= 43) and 1998-2005 (n= 170). RESULTS: The proportion of patients transplanted in first or second complete remission (CR) increased markedly from 21% in 1992-1997 to 52% in 1998-2005. The cumulative incidence of relapse at 1 year post HCT was significantly lower for the later cohort (22% vs 30%, P= 0.04) and for patients transplanted in CR compared with those not in CR (16% vs 31%, P= 0.01). The overall survival probability was significantly better at 5 years post HCT for patients transplanted in 1998-2005 compared with 1992-1997 (40% vs 21%, P= 0.04). Multivariate analysis identified five independent significant favourable factors for survival among the whole patient group: age under 40 years, transplant in CR1, CR2 or first relapse, patient CMV seronegativity, good performance status and year of transplant within 1998-2005. CONCLUSION: The later cohort of patients had improved survival even after allowing for the effects of age, remission status and other factors, which suggests a general improvement in the safety of the procedure over time, particularly for patients in early disease stages at transplant.

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.

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. AIM: To describe allogeneic and autologous bone marrow and blood stem cell transplantation activity and outcomes in Australia and New Zealand from 1992 to 2001. METHODS: Each haemopoietic stem cell transplant centre in Australia and New Zealand contributes information to the Registry via a single information form compiled when a transplant is performed. An annual follow-up request is then sent from the Registry to the contributing centre at the anniversary of each individual transplant. RESULTS: Haemopoietic stem cell transplants in Australia have increased in number from 478 in 1992 to 937 in 2001, whereas in New Zealand the number has grown from 91 in 1998 to 105 in 2001, mainly as a result of an increase in autologous blood stem cell transplants. The number of hospitals contributing to the ABMTRR has grown from 20 in 1992 to 37 in 2001. The most common indication for autologous transplantation in 2001 was non-Hodgkin's lymphoma, whereas for allogeneic transplants it was acute myeloid leukaemia. The 9-year actuarial disease-free survival probability for patients aged 16 and above between 1992 and 2000 was 37% for autologous, 39% for allogeneic related donor and 30% for allogeneic unrelated donor transplants. Recurrence of the underlying disease was the main cause of death post-transplant after both allogeneic (26.3% of deaths in the first year and 68.0% of deaths in the second year) and autologous transplants (59.0% and 86.2%). Treatment-related mortality was 16.9% after allogeneic transplantation and 2.1% after autologous transplantation in 2000. CONCLUSIONS: The ABMTRR provides a comprehensive source of information on the use of bone marrow transplant, and allows for continuing analysis of changes in the application of this high-cost technology and the outcome of patients undergoing these procedures. Registry data provide a means for directing future clinical research into perceived areas of priority for improvement of outcome, such as the reduction in the risk of disease recurrence post-transplant.

Prevalence of malnutrition and 12-month incidence of mortality in two Sydney teaching hospitals.

AIMS: The objectives of the present study were to determine: (i) the prevalence of malnutrition in two Sydney teaching hospitals using Subjective Global Assessment (SGA), (ii) the effect of malnutrition on 12-month mortality and (iii) the proportion of patients previously identified to be at nutritional risk. METHODS: A prospective study using SGA to assess nutritional status of eligible inpatients, from April to September 1997, with a 12-month follow-up to assess mortality. A total of 819 patients was systematically selected from 2,194 eligible patients. Patients were excluded if they were under the age of 18, had dementia or communication difficulties, or were under obstetric or critical care. The main outcome measures were prevalence of malnutrition, 12-month incidence of mortality, proportion of patients identified with malnutrition, and hospital length of stay (LOS). RESULTS: The prevalence rate of malnutrition was 36%. The proportion of malnourished patients was not significantly different between the two hospitals (P = 0.4). The actuarial incidence of mortality at 12 months after assessment was 29.7% in malnourished subjects compared with 10.1% in well-nourished subjects (P < 0.0005). Malnourished subjects had a significantly longer median LOS (17 days vs 11 days, P< 0.0005) and were significantly older (median 71 years vs 63 years, P < 0.0005) than well-nourished subjects. Only 36% of the malnourished patients had been previously identified as being at nutritional risk. CONCLUSIONS: Malnutrition in Australian hospitals is a continuing health concern and is associated with increased LOS and decreased survival after 12 months. The present study revealed that malnourished patients were not regularly identified. Further studies are required to determine whether routine identification of malnutrition and subsequent nutritional intervention are effective in improving clinical outcomes in these individuals.

Allogeneic haemopoietic cell transplants in Australia, 1996--a multi-centre retrospective comparison of the use of peripheral blood stem cells with bone marrow.

A retrospective comparison was carried out on adult patients receiving HLA-identical allogeneic haemopoietic stem cell transplants from siblings in Australia in 1996, comparing bone marrow with G-CSF-mobilised peripheral blood stem cells. A total of 131 transplant recipients from nine centres were included in this study, of whom 79 received bone marrow, 44 blood stem cells and eight both. All but three of the 131 patients had cyclosporin and methotrexate as graft-versus-host disease prophylaxis. The minimum follow-up time for surviving patients is 27 months. Comparisons were carried out between the BM and PBSC groups. There were no significant differences between groups in age, sex, diagnosis, donor characteristics or pretransplant conditioning. Median time to neutrophil recovery of 0.5 x 10(9)/l was 14 days for PBSC recipients, compared to 19 days for marrow recipients (P < 0.0005). median time to platelet recovery of 20 x 10(9)/l was 17 days for PBSC recipients, compared to 28 days for marrow recipients (P < 0.0005). there were no significantly increased risks of either acute or chronic GVHD in the PBSC recipients. there were no significant differences between the groups in the incidence of major transplant-related complications, disease-free survival or overall survival.

Risk taking in patients with rheumatoid arthritis: are the risks of haemopoietic stem cell transplantation acceptable?

OBJECTIVES: Autologous haemopoietic stem cell transplantation (HSCT), which carries defined risks of early treatment-related mortality (TRM), has recently been proposed as an experimental therapy for severe rheumatoid arthritis (RA). The aim of this study was to establish whether the risks of this approach are acceptable to patients with RA and whether risk taking related to disease-associated or personal/social parameters. METHODS: A standard gamble questionnaire was used to determine the acceptable risk of mortality for a potentially curative procedure in patients with RA aged <70 yr. Additional data collected included age, sex, duration of RA, number of second-line agents, domestic and workforce information, and self-assessed disability. RESULTS: The 53 patients (age range 24-69 yr, 39 female, 14 male, disease duration 2-43 yr) interviewed were prepared to accept a broad range of treatment-related mortality in order to be returned to normality off all drugs (median 5%, range 0-50%). Risk taking was significantly related to degree of disability measured by the disability section of the Health Assessment Questionnaire (HAQ; P = 0.001) and negatively related to age (P = 0.04), although only HAQ score maintained significance on multivariate analysis. Using linear regression, we were able to determine that current TRM of autologous HSCT in Australia (3.3%) would be acceptable to patients with HAQ scores of >0.44 (84% of our sample), but allogeneic HSCT (with a TRM of 13.1%) would be acceptable only to severely disabled patients with HAQ scores of >2.45 (4% of our sample), assuming the procedure to be curative. CONCLUSION: Along with previous studies, these results suggest that, if long-term efficacy can be proven, then the risks of autografting may be acceptable to most patients with RA, particularly those with significant disability.

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.

Incidence of deep vein thrombosis after laparoscopic vs minilaparotomy cholecystectomy.

OBJECTIVES: To determine the frequency of deep vein thrombosis (DVT) associated with minimally invasive cholecystectomy and to determine, using minilaparotomy cholecystectomy as a control operation, the influence of the laparoscopic pneumoperitoneum on DVT formation. DESIGN: Prospective nonrandomized control trial. SETTING: Tertiary care university hospital. PATIENTS: One hundred consecutive patients intended to undergo either laparoscopic cholecystectomy (59 patients) or minilaparotomy cholecystectomy (41 patients) with either of 2 surgeons were prospectively enrolled between April 1996 and April 1997. The minilaparotomy cholecystectomy group served as controls to isolate the effect of the pneumoperitoneum. Patient details, operative details, and any thromboembolic or bleeding complications were recorded. The same thromboprophylaxis regimen was prescribed for each group; namely, preoperative and postoperative subcutaneous low-molecular-weight heparin (LMWH), graduated compression stockings, and intraoperative intermittent calf compression. INTERVENTION: Minimally invasive cholecystectomy. MAIN OUTCOME MEASURE: Frequency of DVT. Bilateral lower limb venous color duplex scanning was used to detect DVT. Scans were performed on 3 occasions: (1) preoperatively on admission to hospital, (2) on the first postoperative day, and (3) between 2 and 4 weeks postoperatively. RESULTS: Three patients in the laparoscopic group and 2 patients in the minilaparotomy group underwent conversion to conventional open cholecystectomy. There were no significant differences between patients in the 2 groups for age, sex, body mass index, preoperative white blood cell count, platelet count, prothrombin time, or activated partial thromboplastin time. There were no significant differences between the 2 groups for elective vs emergency operations, public hospital vs private hospital admissions, or consultant vs resident surgeon. Macroscopic gallbladder pathology grades for both groups were not significantly different, and there was no significant difference in the duration of postoperative hospital stay. Operative cholangiography was performed in a significantly larger proportion of laparoscopic cases (86% vs 66% in the minilaparotomy group; chi(2) test, P=.002), and the duration of anesthesia was significantly longer for the laparoscopic operation (118 minutes vs 98 minutes; t test, P=.05). Ninety-seven patients received preoperative LMWH and all patients received graduated compression stockings, intraoperative intermittent calf compression, and postoperative LMWH. Two of the 100 patients had postoperative DVT, 1 after laparoscopic cholecystectomy and 1 after minilaparotomy cholecystectomy. Both DVTs were detected by duplex examination on the first postoperative day. The DVT found after laparoscopic cholecystectomy was in 1 of the 3 patients who did not receive preoperative LMWH. There were no DVTs in any of the 40 patients who had an additional duplex scan between 2 and 4 weeks after operation. CONCLUSIONS: Despite the theoretical risk of thromboembolic disease due to use of the laparoscopic pneumoperitoneum, the frequency of DVT after either laparoscopic cholecystectomy or minilaparotomy cholecystectomy is low if adequate thromboprophylaxis is provided.

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.

Haemopoietic stem cell transplantation in Australia, 1992-95: a report from the Australian Bone Marrow Transplant Recipient Registry.

BACKGROUND: Bone marrow and blood stem cell transplantation is increasingly utilised in Australia. The Australian Bone Marrow Transplant Recipient Registry was founded in 1991 to record this activity. AIM: To describe allogeneic and autologous bone marrow and blood stem cell transplantation in Australia during 1992-95. METHODS: Each bone marrow transplant programme in each State of Australia has been invited to contribute information to the Registry and all do. A single information sheet is compiled by the data manager in each programme when a marrow transplant is performed and mailed to the Registry office. An annual follow-up sheet is then mailed from the Registry to the contributing centre at the anniversary of each individual transplant. RESULTS: Australia-wide, haemopoietic cell transplants have increased in number from 478 in 1992 to 681 in 1995. The number of hospitals contributing registrations to the Australian Bone Marrow Transplant Registry has increased from 20 in 1992 to 25 in 1995. The main reason for the increased number of transplants is an increase in the number of autologous blood stem cell transplants including an increase in the number of staged autologous blood stem cell transplants. The most common indication for a single autologous transplant in 1995 was non-Hodgkin's lymphoma and for a staged autologous transplant was breast cancer. The commonest indication for an allogeneic family member transplant in 1995 was acute myeloid leukaemia and for an allogeneic unrelated donor transplant, acute lymphoblastic leukaemia. The three year actuarial overall survival for patients receiving a haemopoietic stem cell transplant between 1992 and 1994 was 54% with a median follow-up time of 2.04 years. Recurrence of the underlying malignant disease was the main cause of death during both the first and second year post transplant after both allogeneic (13.3% and 8.3%) and autologous (22.1% and 11.8%) transplantation. Treatment-related mortality was 13.1% after allogeneic transplantation and 3.3% after autologous transplantation. CONCLUSIONS: Trends in bone marrow and blood stem cell transplantation practice in Australia during 1992-1995 have been outlined and both practice and outcome can be compared with that in other countries. The main cause of treatment failure, recurrence of the underlying malignant disease, indicates that this is where current and future research needs to be focused.

Lenograstim administration to HLA-identical donor-recipient pairs to accelerate marrow recovery post-transplant.

In an attempt to accelerate marrow recovery after HLA-identical sibling bone marrow transplantation, the donors of 12 patients with haematological malignancy were given recombinant human granulocyte colony-stimulating factor (rHuG-CSF; lenograstim; Granocyte) 5 micrograms/kg/day for seven doses prior to marrow harvest. All 12 recipients also received lenograstim 5 micrograms/kg/day from the day of transplant until their neutrophil count was 1.0 x 10(9)/1. In addition to lenograstim post-transplant and lenograstim-stimulated donor bone marrow the first six recipients also received donor peripheral blood stem cells that had been enriched for CD34+ stem/progenitor cells and T cell depleted on an immune absorption column (cohort 1). The second six patients (cohort 2) received lenograstim post-transplant and lenograstim-stimulated donor marrow only. All 12 patients showed a marked elevation of their circulating white blood cell count (predominantly neutrophils) on day 1 post-transplant. Compared to carefully matched historical control patients the rate of neutrophil engraftment was significantly accelerated in both patient cohorts and platelet engraftment was accelerated in cohort 2.