Infirm Patients Research Articles

Management of small renal masses: a review

Recently, small renal masses (SRMs) (< or =4 cm) are found more frequently, especially in the elderly and co-morbid patients. Standard treatment for SRMs is nephron-sparing surgery (NSS). New techniques like energy ablation and surveillance have been introduced. Overview of treatment options for SRMs, based mainly on the meta-analyses available for NSS, cryoablation, radio-frequency ablation (RFA), and surveillance. NSS for SRMs is the standard therapy with excellent cancer-specific survival rates up to 97%. Cryoablation was mainly performed laparoscopically, and RFA mainly percutaneously. Pretreatment biopsies were used frequently for cryoablation (80%) and less frequently for RFA (50%). Primary failure rate for cryoablation was 4.8% and for RFA 13%. Major complication rates for both procedures are around 5%. Based on 6-month post-ablative biopsies, non-contrast enhancement seems to be an effective surrogate marker after cryoablation, but not after RFA. Follow-up after energy ablation is too short to draw final conclusion. Data on surveillance are based on small, retrospective data with insufficient follow-up. Growth patterns during follow-up do not correlate with the underlying tumour entity. Standard therapy for SRMs is still NSS. Energy ablation should be reserved for the elderly patients with co-morbidities and surveillance for the elderly and infirm patients.

Association Between The Hematopoietic Cell Transplantation-Specific Comorbidity Index (CIn) And Non-Relapse Mortality (NRM) After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (Allo-SCT) For Acute Myeloid Leukemia (AML) In First Complete Remission (CR1)

The adapted Charlson CIn (Sorror-CIn) was useful for predicting NRM and survival in allo-SCT patients. However, the value of this CI index is still under considerable debate, since the cohort used by Sorror et al. (Blood 2005) included a heterogeneous group of patients. On the other hand, toxicities and NRM prediction is most likely needed in elderly and medically infirm patients who are increasingly offered RIC allo-SCT. Thus, the current study was designed to test the performance of this CI and its association with outcomes among a cohort of 345 patients (i) aged >50 y.; (ii) diagnosed with a single disease entity, AML in CR1, and (iii) who underwent a RIC allo-SCT reported to the EBMT registry.

Radiotherapy in the Treatment of Resectable Rectal Adenocarcinoma

The goal of treatment is to cure whereas maintaining sphincter function and minimizing toxicity. Although the mainstay of the treatment is surgery, radiotherapy (RT) is used in a substantial proportion of patients depending on the location and extent of the tumor. The aim of this article is to discuss the role of RT in patients with resectable rectal adenocarcinoma. This article is a review of the pertinent literature. Results show that patients with T1N0 exophytic, well to moderately differentiated, mobile tumors < or = 3 cm in diameter may be treated with either transanal excision or endocavitary RT. The probability of cure with either approach is approximately 80% to 90% and depends on selection criteria. The advantages of endocavitary RT are that it is an outpatient procedure requiring, at most, local anesthesia and is suitable for elderly, infirm patients. The disadvantage is that few of these treatment units are available. Patients who experience a local-regional recurrence may be surgically salvaged. Patients who undergo transanal excision and have unfavorable pathologic findings including equivocal or close margins, poor differentiation, invasion of the muscularis propria, and/or endothelial-lined space invasion have a high risk of local-regional recurrence after surgery alone. The addition of postoperative RT improves the likelihood of cure from 85% to 90%. Patients presenting with unfavorable tumors that are borderline resectable with a transanal excision may be downstaged with preoperative RT and rendered suitable for a wide local excision. The addition of concomitant chemotherapy probably enhances downstaging and may improve the likelihood of sphincter preservation. Patients with T3 and/or N1 rectal cancers have a relatively high probability of local-regional recurrence after surgery alone. Preoperative RT and postoperative RT combined with adjuvant chemotherapy have been shown to significantly reduce the risk of local-regional recurrence and improve survival. Whether preoperative RT alone or combined with chemotherapy is more efficacious than postoperative chemoradiation remains unclear. Endocavitary RT or transanal excision is suitable for patients with T1N0 cancers. Depending on tumor location and extent, adjuvant RT may improve the probability of local-regional control and survival for patients with locally advanced rectal adenocarcinomas.

Association Between the Hematopoietic Cell Transplantation-Specific Comorbidity Index (CI) and Non-Relapse Mortality (NRM) After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) in First Complete Remission (CR1).

Abstract 650The Seattle group previously reported that the adapted Charlson CI (Sorror-CI) was useful for predicting NRM and survival in patients undergoing allo-SCT. However, the value of this CI index is still under considerable debate, since the cohort used by Sorror et al. (Blood 2005; 106:2912-9) included a large age range, a wide variety of diseases, with both myeloablative and RIC transplants. On the other hand, toxicities and NRM prediction is most likely needed in elderly and medically infirm patients who are increasingly offered RIC allo-SCT. Therefore, the current study was designed to test the performance of this CI and its association with outcomes among a cohort of 345 patients (i) aged >50 y.; (ii) diagnosed with a single disease entity, AML in CR1, and (iii) who underwent a RIC allo-SCT reported to the EBMT registry between 1999 and 2006.In this series, the median year of allo-SCT was 2004, and the median age was 58 y. (range, 50-76). 32% of patients needed more than one induction course to achieve CR1. A fludarabine-based RIC regimen was used in 64% of patients, while 31% of patients received low-dose TBI as part of their RIC, and 6% received other non-specified RIC regimens. 76% of the patients received allo-SCT from an HLA-matched sibling donor.Based on score calculated with hazard ratios (HR) estimated on the population studied, 161 patients (47%) had a CI score of 0, 96 patients (29%) had a score of 1, and 49 (14%) had a CI score of 2. The remaining 39 patients (11%) had CI scores of 3 or more. In this cohort, 2 years overall and leukemia-free survival rates were 64±3% and 54±3% and the 2 years relapse and -NRM cumulative incidences were 32±2%, and 15±2% respectively. The 2 years NRM incidences according to comorbidities score 0, 1, 2 and 3+ were 9±2%, 15±4%, 18±5% and 31±7%, respectively. In multivariate models (adjusted for recipient age, donor type, use of TBI or not, and cytogenetics risk group) comorbidities such as moderate active liver disease, obesity, prior history of renal dysfunction, and prior history of severe liver disease were associated with the highest HRs for 2 years NRM (varying from 2.11 to 2.76) and 2 years cumulative incidences of NRM varying from 22% to 44%, whereas previous solid tumor, diabetes, rheumatologic abnormalities, moderate pulmonary diseases, cardiac abnormalities (other than arrhythmia and valve disease) were associated with the lowest HRs (varying from 0.2 to 1.0) with 2 years cumulative incidences of NRM varying from 5 to 17%.Results from this large study performed in a single disease entity and homogeneous allo-SCT setting, suggest that the hematopoietic cell transplantation-specific CI is a simple, informative and useful tool for capturing pre-transplant comorbidities, and for predicting NRM after RIC allo-SCT for AML in CR1 in patients aged >50 y. Such index may be used for clinical trials and patient counselling before RIC allo-SCT. Disclosures:No relevant conflicts of interest to declare.

Nonmyeloablative Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia in the Imatinib Era

Allogeneic stem cell transplantation (ASCT) is a potentially curative treatment for patients with chronic myelogenous leukemia (CML) and was previously considered the preferred treatment for newly diagnosed CML. The success of imatinib has changed treatment recommendations, and allogeneic transplants are now reserved for imatinib treatment failures. Previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. It is unclear whether patients whose disease is considered to have failed imatinib should be referred immediately for ASCT or receive treatment with a second-generation tyrosine kinase inhibitors (TKI). Patients whose disease fails 2 TKIs should receive ASCT if possible. Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions.

Reduced-intensity conditioning transplantation in myeloid malignancies

The development of non-myeloablative and reduced-intensity conditioning regimens has enabled older or medically infirm patients with myeloid malignancies to be treated with allogeneic hematopoietic cell transplantation (HCT). The regimens are sufficiently immunosuppressive to allow engraftment of allogeneic cells and they rely largely on graft-versus-leukemia effects rather than high-dose cytotoxic therapy to eliminate malignant cells. Overall 2-5-year survivals after allogeneic HCT in older patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) have ranged from 25% to 64%. Outcomes were comparable for human leukocyte antigen-matched related and unrelated grafts. The best results were seen in patients transplanted in the first or second remission. Relapse and progressive disease continue to be problems, particularly in patients with large tumor burdens at the time of HCT. Reduction of the tumor burden before HCT with targeted therapy such as radiolabelled anti-CD45 antibody may improve the outcome. Despite still existing problems, early results in elderly patients with AML/MDS have been encouraging.

Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with De Novo and Secondary Acute Myeloid Leukemia

We report the results of 256 patients (median age = 59; range, 5–74 years) with de novo AML in first complete remission (CR1; n=100), beyond CR1 (n=79) and with treatment-related or secondary AML (n=77) who underwent allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related (n=109) or from unrelated donors (n=147). Indications of allogeneic HCT in CR1 were persistent cytogenetic or molecular evidence of disease, poor-risk cytogenetics at diagnosis, treatment-related or secondary AML and age more than 60 years. Younger patients were included if they had comorbid conditions that excluded them from conventional allogeneic HCT. Sixteen patients were mismatched with their donors for ≥ one HLA antigen, while the remainder were matched 10/10 at the antigen level. Conditioning consisted of low-dose total body irradiation (TBI; 2 Gy) on day 0 either alone (n=28) or combined with fludarabine, 30 mg/m2/day on days −4 to −2 (n=228). Calcineurin inhibitors (cyclosporine or tacrolimus) and mycophenolate mofetil were used for postgrafting immunosuppression. Durable engraftment was observed in 94% of patients. With a median follow-up of 35 (range, 3 – 111) months in surviving patients, the estimated progression-free and overall survivals at 5 years were 32% (95% CI: 25–38%) and 32% (95% CI: 25–38%), respectively. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 40% (95% CI: 33–46%) and 29% (95% CI: 22–35%), respectively. Estimated 5-year survival rates, progression-free survival, relapse/progression rate, and non-relapse mortality according to disease status are shown in Table 1; Table 2 shows the same indices according to donor type. The cumulative incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) in patients with related donors were 40% and 13%, and in those with unrelated donors were 58% and 14%, respectively. The cumulative incidence of chronic extensive GVHD at 5 years was 44% in patients with related donors, and 42% in patients with unrelated donors. Age > 60 years at the time of HCT did not have an impact on the outcome (univariate analysis). Additional analyses regarding the impact of HCT comorbidity scores and minimal residual disease at the time of HCT are in progress. Based on this multicenter analysis, we conclude that allogeneic HCT from related or unrelated donors, utilizing a conditioning regimen of low dose TBI (2 Gy) with fludarabine provides long term remission in elderly and/or medically infirm patients with AML, who were not considered candidates for conventional HCT.Table 1. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to disease status. CR1: 1st remission; >CR1: subsequent remission, induction failure/persistent disease; sAML: treatment-related and secondary AML.Disease Statusn%OS (95% CI)%PFS (95% CI)RR (95% CI)NRM (95% CI)CR110033 (20–46)34 (23–46)36 (26–47)30 (19–40)>CR17938 (26–49)35 (23–46)40 (29–52)25 (15–35)sAML7720 (8–32)23 (11–35)45 (32–57)32 (20–45)Table 2. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to donor type.Donor Typen%OS (95% CI)%PFS (95% CI)RR (95% CI)NRM (95% CI)HLA-identical related10934 (23–44)34 (24–45)47 (37–58)18 (10–26)HLA-matched unrelated13131 (22–40)30 (21–39)37 (29–46)33 (24–72)HLA mismatched unrelated1624 (0–50)24 (0–50)6 (0–18)70 (43–97)

Probe ablative treatment for small renal masses: cryoablation vs. radio frequency ablation

Localized renal cell carcinoma has an excellent 5-year survival when treated surgically. Apart from extirpative treatment, ablative techniques are becoming more popular to minimize patient morbidity. Clinically, radio frequency ablation and cryoablation can be performed percutaneously or laparoscopically. Oncological effectiveness of ablative techniques is encouraging as 3-year data are emerging. Our review highlights the current literature demonstrating the effectiveness of cryoablation and radio frequency ablation performed laparoscopically or percutaneously. Cryoablation performed laparoscopically or percutaneously offers excellent oncological outcomes with single-session therapy. With 3-year cancer-specific survival of 98%, laparoscopic cryoablation is safe and can be performed with minimal insult to overall renal function. Local recurrence rates and metastatic progression also seem to favor cryoablation over radio frequency ablation (4.6 vs. 11.7% and 1.2 vs. 2.3%, respectively). Radio frequency ablation also offers similar survival rates; however, re-treatment rates are higher (8.8%). Radio frequency ablation also carries a higher rate of collecting system injuries when performed percutaneously. Cryoablation and radio frequency ablation are effective treatment modalities for small renal masses in the infirm patient. Given patient and technical variability, superiority of either radio frequency ablation or cryoablation cannot be confirmed based on available literature. However, there is a trend towards higher recurrence and re-treatment rates after radio frequency ablation.

Bedsores: "top to bottom" and "bottom to top".

Bedsore is a global problem concerning the bedridden, infirm, debilitated and malnourished patients in hospitals and community setups. The cost of treatment is enormous involving billions of dollars to nations and individuals. Mortality increases two to six times if bedsores are present. There is little research done despite its commonness to understand how they occur or why they occur; etiology is not much understood. The two theories called 'top to bottom' and 'bottom to top' contradict each other. It is thought that 'pressure', shear-stress' and 'ischemia' may be causing it in some yet to be understood way.There is little awareness on how to prevent them or how to treat them if they do occur. Seldom applied, various scales exist and should be used to identify patients at high risk. Braden scale is the most tested and widely accepted scale. The various available dressings and pressure relief devices are mostly inadequately studied; which is superior is a question that begs an answer. This article aims to underline the importance of bedsores by reviewing our current and past knowledge with emphasis on practical implications thereof.

Hematopoietic cell transplantation‐comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation

Elderly and medically infirm cancer patients are increasingly offered allogeneic nonmyeloablative hematopoietic cell transplantation (HCT). A better understanding of the impact of health status on HCT outcomes is warranted. Herein, a recently developed HCT-specific comorbidity index (HCT-CI) was compared with a widely acceptable measure of health status, the Karnofsky performance status (KPS). The outcomes of 341 patients were evaluated, conditioned for either related or unrelated HCT by 2-gray (Gy) total body irradiation given alone or combined with fludarabine at a dose of 90 mg/m(2). Comorbidities were assessed retrospectively by the HCT-CI. Performance status before and toxicities after HCT were graded prospectively using the KPS and National Cancer Institute Common Toxicity criteria, respectively. Weak Spearman rank correlations were noted between HCT-CI and KPS and between the 2 measures and age, number of prior chemotherapy regimens, and intervals between diagnosis and HCT (all r < 0.20). High-risk diseases correlated significantly with higher mean HCT-CI scores (P = .009) but not low KPS (P = .37). In multivariate models, the HCT-CI had significantly greater independent predictive power for toxicities (P = .004), nonrelapse mortality (P = .0002), and overall mortality (P = .0002) compared with the KPS (P = .05, .13, and .05, respectively). Using consolidated HCT-CI and KPS scores, patients were stratified into 4 risk groups with 2-year survivals of 68%, 58%, 41%, and 32%, respectively. HCT-CI and KPS should be assessed simultaneously before HCT. The use of both tools combined likely refines risk-stratification for HCT outcomes. Novel guidelines for assessment of performance status among HCT patients are warranted.

Unstable elbow dislocations

Seventeen patients with a posterior dislocation of the elbow and either no fracture or a minimal capsuloligamentous avulsion fracture were treated operatively for persistent redislocation after manipulative reduction. Fifteen had open reduction and ligament repair (3 with ancillary hinged external fixation), and 2 infirm patients had closed reduction and cross pinning of the elbow joint. Among the 12 patients treated with ligament repair alone, 1 redislocated (treated with a second surgery for hinged external fixation) and 4 had residual subluxation (treated with temporary casting of protected active exercises) after ligament repair alone (42% residual instability). A concentric, stable elbow was eventually achieved in all 17 patients. The average flexion arc was 113 degrees . The average Broberg and Morrey score was 88, with 3 excellent, 10 good, and 2 fair results. A small percentage of elbow dislocations require operative treatment. Ligament repair alone may not be sufficient, and protection with a hinged external fixator is recommended.

Toxicities associated with hyperthermic isolated limb perfusion and isolated limb infusion in the treatment of melanoma and sarcoma

Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) may play a significant role in the treatment of patients with recurrent or in transit extremity melanoma or sarcoma that is unresectable. These procedures may be indicated when patients are otherwise faced with the possibility of a debilitating amputation. Not entirely benign treatment modalities, HILP and ILI can be associated with regional and systemic toxicities. We conducted a literature search of published studies using HILP and ILI for the treatment of extremity sarcomas and melanomas, and associated toxicities was performed.The regional toxicities of HILP and ILI are similar. The most common toxicities reported are mild to moderate. However, when severe regional toxicity occurs, albeit infrequently (<5%), fasciotomies or even amputation may be necessary. Some studies have showed a relationship between acute regional toxicities and long term regional morbidity. Systemic toxicity appears to be more frequent when TNF-α is used in combination with other drugs during HILP, however the use of TNF-α in the United States is limited to trials.Although regional toxicities are similar, systemic toxicity of ILI is minimal compared to HILP. ILI is easier to repeat, technically less complex, and may be more acceptable in infirmed patients. Long term morbidity and outcomes for ILI are still being evaluated. Both of these techniques may be suitable options in patients with unresectable advanced or recurrent, or in transit extremity melanoma or sarcoma.

Preventing Perhexiline Toxicity: Advanced Age But Not Heart Failure as Determinants of Pharmacokinetics

Background:Perhexiline (Px) is a carnitinepalmitoyltransferase inhibitor utilized as a first line anti-anginal agent. However, Px exhibits saturable and genotype-dependent hydroxylation by CYP2D6; prolonged Px accumulation beyond the therapeutic range (0.15–0.60mg/L) induces development of hepatitis and/or peripheral neuropathy. Recently, Px has been utilized particularly for management of patients with “end-stage” ischaemia and/or congestive heart failure (CHF). No pharmacokinetic information is currently available concerning the use in aged and infirmed patients. Methods: In 110 patients treated long-term with Px and achieving stable plasmaPx concentrationswithin the therapeutic range, we investigated the influence of advanced age and CHF on dosage requirements, corrected for metaboliser status. The relationship between Px dosage and steady-statehydroxy-Px:Px (OH-Px:Px) ratiowas evaluated. R y t d i T s M p < d C v C r p C

Early Breast Cancer in the Elderly

Breast cancer is a common tumour in the elderly and management of early disease in particular is a major challenge for oncologists and geriatricians alike. The process should begin with the Comprehensive Geriatric Assessment (CGA), which should be undertaken before any decisions about treatment are made. The important role of co-morbidities and their effect on life expectancy also need to be taken into account when making treatment decisions. The primary treatments for early breast cancer are surgery, adjuvant radiotherapy and adjuvant systemic therapy. Unfortunately, lack of a specific literature relating to early breast cancer in the elderly means formulating an evidence-based approach to treatment in this context is difficult. We have developed a new approach based on the CGA and comprehensive oncological assessment. This approach facilitates the development of an individualized oncogeriatric care plan and follow-up based on several considerations: the average patient's life expectancy at a given age; the patient's co-morbidities, level of dependence, and the impact of these considerations on diagnostic and therapeutic options as well as life expectancy; and the potential benefit-risk balance of treatment. In the elderly patient with breast cancer, the standard primary therapy is surgical resection (mastectomy or breast-conserving therapy). While node dissection is a major component of staging and local control of breast cancer, no data are available to guide decision-making in women aged >70 years. Primary endocrine therapy (tamoxifen) should be offered to elderly women with estrogen receptor (ER)-positive breast cancer only if they are unfit for or refuse surgery. Trials are needed to evaluate the clinical effectiveness of aromatase inhibitors as primary therapy for infirm older patients with ER-positive tumours. Breast irradiation should be recommended to older women with a life expectancy >5 years, particularly those with large tumours, positive lymph nodes or negative hormone receptors. Adjuvant hormone therapy remains a reasonable therapeutic option in elderly women with positive hormone receptor tumours. Aromatase inhibitors have demonstrated a better toxicity profile and effectiveness as adjuvant therapy than tamoxifen in young postmenopausal women but have not been specifically studied in the elderly population. The efficacy of adjuvant chemotherapy for breast cancer has been established by meta-analysis and numerous randomized trials but, again, women aged > or = 70 years have rarely been included in such trials. At present, it is difficult to provide a validated recommendation for use of adjuvant chemotherapy in elderly patients with breast cancer. There are no follow-up recommendations specifically for elderly patients after treatment of early breast cancer. However, American Society of Clinical Oncology breast cancer surveillance guidelines suggest physician office visits every 3-6 months for 3 years, followed by visits every 6-12 months for 2 years, then annually. Women taking aromatase inhibitors should also undergo bone mineral density measurement every 2 years. The new approach to assessment and management of early breast cancer in the elderly outlined in this article should be considered an intermediate step because additional evidence to support clinical practice is still needed. Bearing this in mind, physicians should encourage enrollment of elderly breast cancer patients in clinical trials.

Management of Iron Deficiency Anaemia: Are We Meeting the Guidelines?

Purpose: Iron deficiency anaemia (IDA) accounts to upto 15% of all referrals to gastroenterologists. Inspite of the avilability of well establised guidelines the management of IDA is often suboptimal with most patients, if not at all being incompletely investigated. The diagnostic criteria for IDA vary between published studies. This study was done to review the management of patients with IDA at a district general hospital in UK and determine the pitfalls in the diagnosis and treatment of these patients. Methods: A proforma was devised based on the guidelines laid by the British Gastroenterology Society (BSG) for the management of IDA. Retrospective review of case notes of all patients with a new diagnosis of IDA between January 2005 and December 2006 was carried out. Patients with obvious source of blood loss (melaena, haemtemesis, PR bleed) were excluded form the study. Elderly and infirm patients who were deemed to be not fit for further investigations were also excluded from the study. Results: This retrospective study included 110 patients (24 male, 66 female) with age ranging from 22 yr-80 yr (median age 66 yr). About a third of the patients (29%) presented with gastro-intestinal (GI) symptoms. A majority of the patients (47%) were asymptomatic and IDA was diagnosed following routine blood tests. In 38% of the patients IDA was secondary to GI causes. Non GI causes like menorraghia, epistasis, mechanical heart valve attributed to 12% of cases. 24% of patients with a normal upper GI endoscopy were discharged without any lower GI investigations. In 18% of patients no further investigations were arranged after a normal upper and lower GI endoscopy. 20% patients found to have refractory anaemia were referred to specialist centres for further investigation Most of the patients were managed medically with oral iron (96%) and parenteral iron (29%) therapy. 24% patients received blood transfusion, two thirds of which were not indicated as per hospital blood transfusion guidelines. Long term proton pump inhibitor therapy was indicated in 49% of patients but was presecribed in only 30% of the patients. Conclusion: Overall adherence to the BGS guidelines was poor. A care pathway to guide physicians for investigating and treating patients with iron deficiency anaemia was recommended. If a GI cause for IDA is not found after a bidirectional endoscopy then it is necessary to proceed with further investigations to look for non GI causes.

The Beneficial Effect of Chronic Graft-versus-Host Disease on the Clinical Outcome of Transplantation with Fludarabine/Busulfan-Based Reduced-Intensity Conditioning for Patients with De Novo Myelodysplastic Syndrome

Allogeneic hematopoietic stem cell transplantation following reduced-intensity stem cell transplantation (RIST) has enabled the treatment of older or medically infirm patients with myeloid malignancies; however, determining the value of RIST outcomes for myelodysplastic syndrome (MDS) is difficult because of the heterogeneity of the diseases included in most trials. To define the role of RIST in MDS, we performed RIST for 22 consecutive patients who had de novo MDS as classified by World Health Organization (WHO) criteria and who received an allograft with fludarabine/busulfan (Busulfex) or fludarabine/Busulfex/antithymocyte globulin (ATG) conditioning. Nineteen patients (86.4%) achieved engraftment. At a median follow-up of 18.9 months (range, 13.1-24.8 months), the estimated 2-year rates of overall survival, event-free survival (EFS), transplantation-related mortality, and relapse were 78.7%, 67.7%, 12.6%, and 22.5%, respectively. Acute graft-versus-host disease (GVHD) greater than grade II developed in 3 patients (15.8%). Chronic GVHD developed in 10 patients (55.6%), none of whom received ATG as a conditioning regimen. Variables influencing EFS were chronic GVHD, marrow blasts before transplantation, and the WHO criteria. The present study clarifies the benefits of the fludarabine/Busulfex-based conditioning regimen for de novo MDS diagnosed according to the WHO criteria and shows that chronic GVHD appears to have a beneficial effect on survival rates, which are strongly associated with graft-versus-tumor effects.

Reduced-Intensity Transplantation in the Treatment of Haematological Malignancies: Current Status and Future-Prospects

The concept of reduced intensity conditioning (RIC) in allogeneic transplantation had challenged our conventional wisdom about the necessity of high-dose chemo-radiotherapy in order to achieve donor engraftment. The feasibility of RIC in elderly and infirm patients who would not otherwise be considered suitable for a conventional allogeneic transplantation caused a surge of interest in RIC procedures in the late 90s and early part of this decade which was however, not tempered by the balanced need for clinical trials. Although the initial expectations of reduction in graft-versus-host-disease (GVHD) were belied by the high incidences of GVHD, the importance of GVHD, particularly chronic, in controlling haematological malignancies with poor prognosis was often well exemplified. In addition, the conventional outcome measures in allogeneic transplantation such as 100- day mortality became irrelevant in the era of RIC due to reduction in early regimen-related toxicities. This did not always translate to improved overall survival due to late attritions from relapse, GVHD or late infectious complications. The enthusiasm for performing RIC in malignant diseases seems to have reached a plateau, but its true potential probably remains unexplored. In light of our current understanding of RIC, this article will highlight the future of this procedure in haematological malignancies.

RS03 VASCULAR SURGERY IN A RURAL PRACTICE – THE CASE FOR

Centralisation of principal vascular services to tertiary centres has great merit in enabling adequate specialist numbers to provide an acute service with appropriate support facilities. Demand on this vascular service is expected to increase almost 100% with the aging population over the next 20 years. The demography of the population of New Zealand and Australia is such that providing vascular services only in tertiary centres has great potential to disenfranchise many patients living in rural areas. Unless the overall provision of service is excellent, providing an excellent service for only part of the population is untenable.A purely centralised, regional service will have difficulty providing satisfactory care for elderly infirm patients, with limited mobility, who live in rural areas. General Surgeons with no vascular training, working in provincial or rural hospitals cannot be expected to spend the significant time required to triage patients with possible peripheral vascular disease simply to refer them on to vascular surgeons in distant tertiary centres. Many aspects of vascular surgery, relating both to patient assessments and operative procedures do not require tertiary facilities and have historically been competently performed by general surgeons. There are also occasions when our colleagues in other specialities require urgent interventional support for vascular complications. There remains a need in smaller centres for general surgeons with some vascular training to provide this local service supported by, and supporting, colleagues in tertiary centres.

Donor CD34+ Cell Chimerism at Day 28 and Chronic Graft-Versus-Host Disease (GvHD) but Not High-Risk Cytogenetics Influence Outcome of Allogeneic Hematopoetic Cell Transplantation (HCT) Following Reduced Intensity Conditioning (RIC) in Patients with AML and MDS.

HCT after RIC is used increasingly to treat older or infirm patients with AML or MDS. In the current analysis we looked for risk factors influencing outcome including cytogenetics, kinetics of donor CD34+ and T-cell chimerism (CC).Patients and methods: From July 1998 - December 2005, 119 consecutive patients [66 m/53 f; median age 60 (range 21–74) years] with AML (n=99; 83%) and high-risk MDS (n=20; 17%) were treated within the OSHO AML studies before HCT. Seventy (59%) of the patients had intermediate-risk cytogenetics and 44 (37%) high-risk cytogenetics. Patients were either in CR1 (n= 66; 55%), CR2 (n=18; 15%), >CR2 (n=28; 24%), or were untreated (n=7; 6%) at transplant. HCT was performed from matched related (n= 33; 28%) and matched unrelated (n= 86; 72%) donors after RIC (200cGy TBI + fludarabine 30 mg/m2/day on 3 consecutive days) and followed by immunosuppression with cyclosporine and mycophenolate mofetil. Marrow donor chimerism was determined in T-, and CD34+−cells at days (d) 28, 56, 84, and thereafter at 3 month intervals using either XY chromosome FISH in gender mismatched, or PCR based analysis of polymorphic micro satellite regions in gender matched HCT.Results: Engraftment was documented in 112 (94%) of the 119 patients. Survival (OS), disease free survival (DFS), relapse incidence (RI), and non-relapse mortality (NRM) of engrafted patients was 40%, 38%, 46%, and 30% at 3 years respectively. In multivariate analysis, only >90% donor CD34+ CC at d 28, chronic GvHD, and CR1, but not cytogenetic risk factors were associated with an improved OS and DFS. Patients with >90% donor CD34+ CC at d 28 (group I) had an OS of 50% compared to 9% in patients with donor CD34+ CC <90% (group II) (p=0.002). Accordingly, RI in group I was 35% compared to 85% in group II (p<0.0001). Again, donor CD34+ CC at d 28 but neither donor T-cell chimerism nor high-risk cytogenetics correlated with relapse. Relapse occurred in 41/109 (38%) patients at a median of 121 d. All patients (n=19) with haematological relapse within 100 days post transplant died despite reduction/withdrawal of immunosuppression. Of the 22 patients with later relapse, six went into permanent complete remission by reduction/withdrawal of immunosuppression. A decrease of CD34+ chimerism was detected in a further six patients and all responded to a decrease in immunosuppression. The incidence of acute (grades ≥ I) and chronic (limited and extensive) GvHD was 50%, and 55% respectively. OS was 10%, 46%, and 62% for patients with no GvHD (A), acute GvHD only (B), and chronic GvHD (C) (p=0.0001). DFS for A, B, C was 20%, 38%, and 55% respectively ((p=0.0001). RI was highest for A (72%) compared to B (49%) and C (25%) (p<0.0001).Conclusions: HCT after RIC offers long-term OS and DFS in AML/MDS even in patients with high-risk cytogenetics. CR1, donor CD34+ CC >90% at d 28 and chronic GvHD correlate with an improved outcome and decreased relapse incidence. Careful monitoring of donor CD34+ CC can identify patients at risk for relapse, thereby allowing early immunmodulation.

High Level of Pretransplant Leukemic Blasts and the Absence of Chronic Graft-Versus-Host Disease Provide Negative Effects on Clinical Outcome of Transplantation with Fludarabine-Busulfex Based Reduced Intensity Conditioning for Patients with the De Novo Myelodysplastic Syndrome According to WHO Criteria.

Background: Allogeneic hematopoietic cell transplantation (HSCT) is the only curative potential for patients with MDS. HSCT following reduced-intensity conditioning (RIST) have enabled the extension of transplantation to include older or medically infirm patients with myeloid malignancies. However, it is very difficult to determine the value of outcomes of RIST for myelodysplastic syndrome (MDS) because of the heterogeneity of diseases included in most trials and the small number of MDS.Method: Twenty-two patients with de novo MDS classified by WHO criteria received an allograft using a Fludarabine (30 mg/m2/day for 5 days)/Busulfex (3.2 mg/kg/day for 2 days) (14 patients) or Fludarabine (30 mg/m2/day for 5 days)/Busulfex (3.2 mg/kg/day for 2 days)/ATG (2.5 mg/kg/day for 2 days) (8 patients). The median age of patients was 43 years (range, 16–55). Donors were HLA-compatible sibling (n = 19) or matched unrelated (n = 3).Result: Nineteen patients (86.4%) achieved engraftment. At a median follow-up of 18.9 months (range, 13.1–24.8 months), the estimated 2-year overall survival (OS), event-free survival (EFS), transplantation-related mortality and relapse incidence were 78.7%, 67.7%, 12.6%, and 22.5%, respectively. Acute GVHD greater than grade II was developed in 3 patients (15.8%). Chronic GVHD were developed in 10 patients (55.6%) and all of them did not receive ATG as conditioning. Variables influencing EFS were chronic GVHD (None/Limited [20.8%] versus Extensive [100%], P = 0.001), marrow blasts before transplantation (<10% [85.1%] versus >10% [20.8%], P = 0.006), and WHO criteria (RA [100%] versus RCMD [75%] versus RAEB-1 [80%] versus RAEB-2 [20.8%], P = 0.043).Conclusion: These observations indicate that high level of pretransplant leukemic blasts and the absence of chronic graft-versus-host disease provide negative effects on clinical outcome of transplantation with Fludarabine-Busulfex based reduced intensity conditioning for patients with the de novo myelodysplastic syndrome according to WHO criteria.