Reduction In Treatment-related Mortality Research Articles

Acute myeloid leukemia induction in the age of novel therapeutic agents

Acute myeloid leukemia (AML) is a malignant neoplasm of the myeloid lineage characterized by the uncontrolled proliferation of immature myeloid blasts in the bone marrow and peripheral blood. AML is a heterogenous disease which occurs across the age spectrum, although with an increasing incidence with age. For decades, first-line, curative-intent therapy has been based on intensive therapy with anthracycline (typically daunorubicin or idarubicin) plus cytarabine (3+7), followed by additional consolidative chemotherapy and/or allogeneic stem cell transplantation. While improvements over the decades in overall survival have been observed, until recently this has been driven largely by advancements in supportive care leading to reduction in treatment-related mortality and allowing a greater proportion of patients (particularly older individuals) to safely undergo intensive therapy induction and consolidation. Despite this, five-year overall survival (OS) rates in older individuals are as low as 5% (age > 70). Although OS for patients age 15-39 is now in the range of 50%-60%, a large portion of patients still succumb to their disease. Cytogenetic and molecular profiling has led to defined risk categories, and complete risk stratification for all patients eligible for intensive therapy is crucial to aiding in the selection of optimal induction and post- remission therapy. In recent years, an improved understanding of AML biology and genetics has led to the approval of a number of novel therapies for patients deemed fit and unfit for intensive therapy, which may finally be moving the needle beyond 3+7. This article will review a current approach to AML induction patients eligible for intensive therapy, with a focus on the utilization of available novel agents.

Three Decades of Autologous Stem Cell Transplantation for Myeloma; Trends in Early Mortality and Survival

Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to the availability of newer more effective therapies. Autologous stem cell transplantation (ASCT) has been used for over three decades to treat multiple myeloma. We aimed to evaluate the outcome of patients receiving ASCT at our institution between 1990 and 2015.Patients and Methods: A total of 2025 patients received ASCT at Mayo Clinic Rochester between 1st January 1990 and 31st December 2015. The patients were divided in to three cohorts of approximately equal time period, Cohort 1 (1990-1999, n=144), Cohort 2 (2000-2009, n=909) and Cohort 3 (2010-2015, n=972). Outcomes of interest were early mortality, progression free survival (PFS) and overall survival (OS). Disease characteristics were documented from time of diagnosis and PFS and OS were calculated from date of ASCT unless otherwise stated.Results: Median age for the whole cohort was 60 years (range 24-77) and increased over time (55 Cohort 1 vs 59 Cohort 2 vs 61 Cohort 3, p<0.0001). The proportion of males (60% for whole cohort) was not significantly different between the 3 time periods. Almost all patients (99%, n=2018) received chemotherapy prior to transplantation (median lines of therapy 1, range 0-6). The number of patients receiving >1 line of therapy prior to transplantation decreased over time (67% Cohort 1 vs 27% Cohort 2 vs 34% Cohort 3, p<0.0001). The use of novel agents was congruous with their availability and increased over time (0% Cohort 1 vs 59% Cohort 2 vs 100% Cohort 3, p<0.000).After a median follow up of 84 months (95% CI, 78-91 months), median PFS and OS for the whole cohort were 24 and 66 months respectively. Both PFS and OS improved significantly over time (median PFS: 12 months Cohort 1vs 18 months Cohort 2 vs 33 months Cohort 3, p<0.0001; median OS: 26 months Cohort 1vs 63 months Cohort 2 vs 83 months Cohort 3, p<0.0001), Figure 1. The improvement in PFS and OS over the 3 time periods was seen in patients receiving early (≤ 12 months from diagnosis) and delayed (>12 months) ASCT, Table 2. OS from diagnosis was no different for early versus delayed transplant in Cohort 1 and Cohort 2 (Cohort 1: median OS 57 months for early vs 56 months for delayed, p=0.24 and Cohort 2: median OS 81 months for early vs 82 months for delayed, p=0.70) and showed a trend towards a marginal benefit for delayed transplant in Cohort 3 (median OS 105 months for early vs 109 months for delayed, p=0.046).Treatment related mortality (100 days post transplant) improved over time (7.6% Cohort 1 vs 1.8% Cohort 2 vs 0.7% Cohort 3, p<0.0001), Figure 2A. Mortality within 12 months of ASCT also improved over time (24% Cohort 1vs 8% Cohort 2 vs 6% Cohort 3, p<0.0001). A landmark analysis of OS from 12 months post ASCT continued to reveal improved survival over time(median OS 26 months Cohort 1vs 63 months Cohort 2 vs 83 month Cohort 3, p<0.0001), Figure 2B.Conclusion: ASCT remains an important therapeutic option for eligible patients with multiple myeloma. There has been a marked improvement over time in PFS and OS and reduction in treatment related mortality and early mortality in myeloma patients receiving ASCT. This is likely to reflect the addition of novel agents to induction regimens and improved post transplant therapies. Despite these improvements myeloma remains incurable with patients continuing to relapse and die many years after ASCT. [Display omitted] DisclosuresDispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; annexon: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; Ionis: Honoraria; Teva: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Prothena: Honoraria.

Preliminary Outcomes of Children and Young Adults with Acute Lymphoblastic Leukaemia and Down Syndrome (DS-ALL) on UKALL 2011. Reduction in Treatment-Related Mortality with De-Escalated Therapy

IntroductionReported outcomes for children with Downs syndrome (DS) and acute lymphoblastic leukaemia (ALL) treated on our previous national study, UKALL 2003, were inferior compared to non-DS children. 5 year event free survival (EFS) for DS children was 65.6% vs. 87.7% for non-DS children and 5 year overall survival (OS) was 70.0% vs. 92.2% (British Journal of Haematology 2014; 165: 552-555). Excess treatment related mortality (TRM, 21.6% vs. 3.3% at 5 years) in children with DS-ALL was primarily due to infection. Similar results have been reported by other study groups.In our successor study, UKALL 2011, we employed several steps of de-escalation for DS-ALL patients compared to standard therapy. Here, we report that de-escalated therapy has resulted in a dramatic reduction in TRM for children with DS-ALL treated in the UK. MethodsDS-ALL patients treated on UKALL 2011 had their treatment modified in the following respects: 1)NCI high risk patients did not receive anthracycline in induction unless they had a slow early response at day 15; 2) two years maintenance was given for both boys and girls; 3) no pulses were given in maintenance for MRD low risk patients.In addition, we recommended use of prophylactic antibiotics during induction and intensive phases of treatment. Fisher's exact test was used to compare induction mortality in the DS and non-DS pts. OS was defined as time from registration to death. EFS was defined as time from registration to first event (induction failure, relapse, second malignancy or death from any cause). The Kaplan-Meier method was used for survival estimation. ResultsThe UKALL 2011 trial opened to recruitment on 26th April 2012 and has recruited 2362 patients, of whom 50 have Down syndrome, in the period up to 22nd February 2018. The study is open in 41 centres in UK and Ireland and included patients with both ALL and lymphoblastic lymphoma (LBL). The baseline characteristics of the patients recruited up to this date are shown in the table below. For DS-ALL, Day 29 MRD was available for 48 patients and was low risk in 25 cases (50%), risk in 19 (38 %) and no result was obtained in 4 (8 %). The therapy was generally well-tolerated, there have been no cases of therapy curtailment due to toxicity and only one patient due to receive intensified therapy per MRD risk assessment was unable to escalate due to toxicity.At a median follow-up of 32.7 months, there have been 4 events. These include two relapses (relapse rate: 4.1% (1.1-15.5) at 3 years) and two TRMs (one TRM in induction and the other in consolidation; both due to infection). Three year EFS is: 92.9% (95% CI: 79.1 - 97.7) with a three year OS of 95.9% (84.5 - 99.0). The remarkably low induction TRM for DS children on UKALL 2011 (1 death out of 50 patients, 2%), is comparable to that of non-DS children treated on the same protocol with a 3 drug induction (12 out of 1174 children, 1% induction TRM; induction TRM in DS-ALL vs non-DS-ALL p=0.42). It is also comparable to the induction TRM in DS-ALL noted in the latter half of the UKALL 2003 study (1/40, 2.5%) when the aforementioned treatment modifications were first implemented in the UK.Importantly, this TRM is a quarter of that when an historic cohort of DS-ALL children were treated with a 4-drug induction on our previous study (UKALL 2003, DS-ALL TRM 4/46 patients i.e. 8 %, p=0.19). ConclusionThese preliminary results suggest that de-escalation of treatment is successful in reducing treatment related mortality for children with DS-ALL without increasing the risk of early relapse, however longer term follow-up is needed. DisclosuresGhorashian:Celgene: Other: travel support; Novartis: Honoraria. Hough:University College London Hospital's NHS Foundation Trust: Employment. Kearns:Pfizer: Consultancy, Research Funding; Galen: Research Funding. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.

Outcome of allogeneic transplantation in newly diagnosed and relapsed/refractory multiple myeloma: long-term follow-up in a single institution.

Allogeneic stem cell transplantation (allo-SCT) has the potential to induce long-term remission in multiple myeloma (MM), but the role of allo-SCT in MM is controversial due to the high rate of treatment-related mortality (TRM). However, although proteasome inhibitors and immunomodulatory drugs have improved the outcome of patients with MM, high-risk patients still have a very poor prognosis. This indicates the need for new treatment strategies and identification of patients who might benefit from allo-SCT. We therefore analyzed the outcome of one hundred and forty-seven patients with MM who received an allo-SCT at our institution (58 in first line, 89 in relapsed/refractory setting) after a median follow-up of 88.8 months. For the first-line setting, median progression-free survival (PFS) and overall survival (OS) were remarkably good, with a CR rate of 48.3%, median PFS of 30.2 months, and 10-yr OS of 51%. We found no difference in outcome for patients with high-risk metaphase cytogenetics or FISH del(13q14), but efficacy in current standard high-risk patients could not be determined. The outcome in the relapsed/refractory setting was poor, especially in the subgroup of patients relapsing within 18 months after auto-SCT. Therefore, if applied at all in these patients, improvement of allo-SCT is needed, focusing on reduction of TRM and more effective immunotherapy.

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission: Are We Closer to Knowing Who Needs It?

Acute myeloid leukemia (AML) is a very heterogeneous disease. Prognosis is related not only to intrinsic characteristics such as cytogenetics and molecular markers, but also the patient's ability to tolerate therapy, and treatment response. Allogeneic stem cell transplantation (allo-HCT) has been traditionally indicated for poor-risk disease in first complete remission (CR1) or for treatment of relapsed or refractory AML. 'Poor-risk' disease is now better defined due to genetic subtyping, particularly in chromosomally normal AML. In addition, the presence of comorbid conditions should be included in the decision-making process. Improvements in supportive care and the use of modern conditioning regimens have been associated with improved outcomes, mostly due to a reduction in treatment-related mortality. Therefore, a significant proportion of patients with AML-CR1 can potentially benefit from allo-HCT. We give general guidelines on how to incorporate cytogenetic and molecular risk factors, donor selection, and patient characteristics in order to determine when allo-HCT should be indicated in CR1.

Haploidentical Transplantation As Salvage Therapy For Disease Relapse After Allogeneic Hematopoietic Cell Transplantation

IntroductionTherapeutic options and outcome for patients with relapse after allogeneic hematopoietic cell transplantation (HCT) are poor. For individual patients, a second or even third allogeneic HCT can be considered with curative intention. However, treatment-related mortality (TRM) and the risk of relapse after secondary allogeneic HCT are high. Therefore, the use of a haploidentical graft allowing for profound NK- and T-cell-alloreactivity after a reduced-intensity conditioning regimen (RIC) may optimize disease control by enabling potent graft versus leukemia effects and reduction of TRM. MethodsWe here retrospectively evaluated 26 consecutive patients undergoing haploidentical HCT as second (n=24) or third (n=2) allogeneic HCT at our center between 2003-2012. Diagnoses comprised relapse of AML (n=17) or ALL (n=7), blast crisis of CML (n=1) and transplant failure (n=1). There were 16 male and 9 female patients with a median age of 36 years (range 18-59). ResultsFor RIC, fludarabin, thiotepa and melphalan were used in 16 patients, clofarabin, thiotepa and melphalan in 6 patients and other regimens containing variable combinations of cyclophosphamide, busulfan, TBI and treosulfan in 4 patients. Grafts were manipulated by CD3/CD19 depletion (n=19), TCRαβ depletion (n=1) or CD34 selection (n=6) and consisted of a median of 7.71 x 106 CD34+cells/kg bodyweight.The median interval from first HCT to second HCT was 18 months (range 5-145), and 10 and 16 months from second HCT to third HCT in the two patients undergoing a third HCT. Only 35% (n=9) of the patients receiving a second HCT were in complete remission (CR), while 65% (n=16) were in partial remission (PR). Among the patients receiving a third HCT, one had active disease, while the other was in CR. All patients achieved engraftment of the neutrophils at a median time of 11 days (range 8-26) and platelet engraftment was reached at a median time of 15 days (range 9-35, except one patient at day 375). At present, 5 patients (19%) are alive and in CR with a median follow-up of 1870 days (range 281-3941), while 35% (n=9) died from relapse; non-relapse-mortality was 46% (n=12). Kaplan-Meier estimated overall survival for all patients at 1 year was 33% (52% for patients in CR versus 18% in PR) and at 3 years 17% (26% for patients in CR versus 12% in PR). Causes of death in patients with second HCT included severe infections (n=8), organ failure (n=1), haemorrhage (n=1) and progressive multifocal leukoencephalopathy (n=2). Of the patients with third HCT, one died from respiratory insufficiency due to pulmonary haemorrhage, the other is still alive and in CR.Acute graft versus host disease (GVHD) occurred in 11 patients with predominantly mild presentation (grade 1: n=9, grade 2: n=2), limited chronic GVHD was apparent in 5 patients with no case of extensive GVHD. ConclusionHaploidentical HCT is a feasible salvage concept for patients with relapse after HCT with promising results even in patients not in CR. Disclosures:No relevant conflicts of interest to declare.

Declining Rates of Treatment-Related Mortality in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Given “Intensive” Induction Regimens: A Report From the Southwest Oncology Group (SWOG) and MD Anderson Cancer Center (MDA)

AbstractAbstract 129 BackgroundRecent emphasis has been placed on administration of induction regimens less intense than standard 3+7 for patients with newly diagnosed AML. A primary goal is to reduce the presumed average treatment related mortality (TRM) rate of 10% occurring within the first 28 days after start of 3+7 or higher intensity therapies; TRM rates have been > 30% in patients who are older and/or have poor performance status (PS]. (Walter et al. JCO 2012). This practice presupposes that TRM rates with higher intensity induction regimens are static, a notion seemingly difficult to reconcile with advances in supportive care (e.g. newer anti-aspergillosis drugs) that have sharply reduced rates of non-relapse mortality after allogeneic hematopoietic cell transplant (Gooley et al. NEJM 2010). MethodsWe thus addressed rates of TRM from 1991–2009 in 1,409 patients given 3+7 induction regimens on SWOG protocols (cytarabine dose 100 mg/m2 daily × 7) and 1,933 patients given induction regimens containing higher cytarabine doses (at least 1.0 g/m2 daily × 4–5 days) at MDA, variably combined with idarubicin, fludarabine or other agents. Multivariate analyses were used to account for confounding factors. ResultsTRM rates declined both in SWOG and at MDA.PeriodGroupPatientsTRMMedian AgePS < ECOG 21991-1995SWOG39218%6469%MDAa10216%5860%1996-2000SWOG40613%6584%MDA63814%6065%2001-2005SWOG11312%5881%MDA7329%5980%2006-2009SWOG4983%4987%MDA4614%5686%a1995 onlyHowever this reduction must account for the declining ages of patient given 3+7 or more intense induction (p<0.001 in both SWOG and at MDA) and their improved PS (p<0.001 SWOG and MDA);the considerably younger nature of SWOG patients during 2006–2009 reflects the switch to less intense induction regimens for many older patients; such regimens were not included in this analysis. Additionally other covariates associated with TRM (more blood blasts, lower platelets, secondary AML) by Walter et al. (JCO 2012)were unevenly distributed in the various time periods(for example no secondary AML in SWOG 2006–2009). Multivariate logistic regression was thus performed to account for the effect of age, PS, and these other covariates in the reduction in TRM. After such accounting, odds ratios (ORs) for TRM at MDA were (relative to 1995) 0.89, 0.7, and 0.36 for 1996–2000,2001–2005, and 2006–2009 respectively with the null hypothesis of no change over time rejected at p = 0.006. For SWOG, not including secondary AML as a covariate ORs were (relative to 1991– 1995) 0.75,0.78, and 0.42 for 1996–2000,2001–2005,and 2006–2009 respectively; again the hypothesis of no change with time was rejected (p = 0.037). There were no interactions between reduced TRM and age, WBC or performance status suggesting the reduction in TRM was a general phenomenon. ConclusionThere has been a reduction over time in TRM after “intensive” induction possibly due to better supportive care. Although various selection biases cannot be excluded, this decline is not due to younger age or better performance status and needs to be considered when choosing AML induction therapy. Disclosures:No relevant conflicts of interest to declare.

Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia

Royal Bournemouth Hospital, Bournemouth, 2 Royal Marsden Hospital, London, 3 Southampton General Hospital, Southampton, Cardiff and Vale NHS Trust, Cardiff Cambridge University Hospitals NHS Foundation Trust, Cambridge UK; St. James's Institute of Oncology, Leeds, Christie Hospital NHS Trust, Manchester Royal Marsden Hospital London; Heart of England NHS Foundataion Trust, Birmingham; 10 Royal Liverpool University Hospital, Liverpool; Churchill Hospital, Headington, Oxford, Norfolk and Norwich University Hospital, Norwich

Elevated Absolute Lymphocyte Counts Following Acute Graft Vs. Host Disease Treatment Is Associated with Therapeutic Responses and Lower Non-Relapse Mortality Following Umbilical Cord Blood Transplant,

Abstract 4085Acute graft vs. host diseases (aGVHD) is a life threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). In a large series of patients undergoing allo-HCT (n=863) we recently demonstrated that following the initiation of corticosteroids, a clinical response at day 28 was associated with an increased likelihood of overall treatment response and a reduction in treatment related mortality (TRM) (MacMillan, Blood, 2010). We have also shown that patients who have rapid lymphocyte recovery following umbilical cord blood transplantation (UCBT) have improved outcomes (Burke, BBMT, 2010). To date, no study has addressed the influence of absolute lymphocyte count (ALC) on aGVHD treatment responses. We hypothesized that high ALC might predict favorable responses to aGVHD therapy. To test this hypothesis we reviewed the ALC at the time of aGVHD diagnosis and weekly following the initiation of corticosteroid therapy (48 mg/m2 × 14 days followed by a 10% taper over 8 weeks). ALCs were collected on patients who had clinical laboratory data available in the electronic medical record and who had available data on clinical response to corticosteroid therapy. There were 211 patients transplanted at our center from 2001–2007 who fit the above criteria. Median age was 42 years (range 0.2–69 yrs). Thirty nine patients (19%) were <18 years of age and 135 (64%) were >35 years old. The majority of patients underwent UCBT (n=134, 64%) and most others received a sibling PBSC transplant (n=71, 34%). Myeloablative conditioning was used in 55% of patients. GVHD prophylaxis was mainly with CSA/MMF (n=142, 67%) or MTX/CSA (n=42, 22%). Median time to aGVHD onset was 37 days (11–92). Patterns of aGVHD included skin only (n=91, 43%), gut only (n=36, 17%) or multi-organ involvement (n=82, 39%). At the time of GVHD diagnosis, ALC was not predictive of response to therapy. Likewise, there was no association with the ALC at D7 (after the start of steroid treatment) and therapeutic response. The D14 post-treatment ALC showed an association with clinical response at D28 (a time point previously associated with long-term responses and NRM). Patients with an ALC of 0–0.14, 0.15–0.34 and >0.35 at D+14 after corticosteroid therapy had a 40%, 54% and 68% chance of a clinical response at D28 (p>0.01). This translated into a reduction in non-relapse mortality for patients with higher ALC (0–0.14 vs. >0.15; 33% [19–47%] vs 23% [17–29%], p=0.04). Subgroup analysis showed that these observations were mainly driven by the myeloablatve UCB group. Treating ALC as a continuous variable and using a repeated measures approach, we observed that for every unit increase in ALC between the day of diagnosis and D14, there was a 2.26 higher increased likelihood of having a complete clinical response at D28 (p>0.001). Similar results were seen for NRM (OR=0.89 [0.81–9.8], p=0.01). In multivariate analysis, repeated measures of ALC (from D0-14) remained significant for both D28 clinical response (p=0.001) and NRM (p=0.05). Patients with steroid refractory aGVHD (n=17) were treated with ATG. Because steroid refractory aGVHD has poor outcomes and because ATG can negatively impact ALC, we removed these patients from the analysis to determine the impact of ALC. In this subgroup analysis, ALC at D14 after aGVHD treatment remained associated with D28 clinical response in multivariate analysis (OR=3.01, 95%CI[1.24–7.35], p=0.02). Using repeated analysis, the change in ALC from aGVHD treatment day D0 to 14 was associated with D28 treatment response (OR=4.42 [1.88–10.37], p<0.001). Collectively, these results show that absolute ALC at D14 and increases in ALC from the day of treatment to day 14were associated with D28 clinical response and NRM. ALC maybe a simple and cost effective method to monitor response to aGVHD therapy. Disclosures:No relevant conflicts of interest to declare.

Long-Term Outcomes of Myeloid Growth Factor Treatment

Myeloid growth factors are used to reduce myelotoxicity and the risk of infection after cancer chemotherapy and in patients with chronic neutropenia. This article addresses the long-term benefits and risks associated with granulocyte colony-stimulating factor (G-CSF) therapy in both settings. A systematic review of randomized controlled trials recently reported long-term outcomes regarding the risk of second malignancies and overall survival. Based on these studies, the risk for acute myeloid leukemia (AML) associated with known carcinogenic agents, such as chemotherapy, could not be distinguished from any risk associated with growth factor support. However, the enhanced delivery of chemotherapy dose intensity enabled by the use of G-CSF in these studies was associated with a significant reduction in all-cause mortality. Although some reduction in treatment-related mortality with G-CSF support may occur, the observed improvement in long-term survival likely relates to better disease control with more-intense G-CSF-supported chemotherapy. Myeloid growth factors have also been shown to benefit patients with severe chronic neutropenia. Almost all patients with cyclic, congenital, or idiopathic neutropenia experience response to G-CSFs. Treatment is titrated to determine a dose that provides a safe elevation in neutrophil counts. Reports have shown that patients can be maintained for years at the same dose after adjusting for growth and development. In congenital neutropenia, the inherent risk of developing myelodysplastic syndromes or AML requires careful monitoring, including routine blood counts and annual bone marrow examinations.

Novel Preparative Regimens in Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation is an established treatment modality for malignant and non-malignant diseases. Prior to the infusion of allogeneic or autologous cells, patients usually receive radiation or chemotherapy. This "preparative" or 'conditioning' regimen provides treatment for the underlying disease and is expected to impair the recipient's immune system and allow engraftment. The last decade witnessed a significant reduction in treatment-related mortality, in great part a result of less toxic preparative regimens and improvements in supportive care. Another important trend has been the incorporation of newer drugs to 'classic' conditioning regimens, as illustrated by the addition of rituximab to BEAM and other combinations. It is expected that this trend will continue leading to increased cure rates by incorporation of targeted therapies to hematopoietic transplant. The next decade will likely witness further integration of new preparative regimens with graft engineering, and pharmacologic, cellular and immunologic post transplant interventions. The design of creative clinical trials that will allow the critical evaluation of the role of these new approaches in transplantation will also be a major challenge to the transplant community in the years to come. In this article, we review newer transplant conditioning regimens and discuss their indications and future directions in this rapidly changing landscape.

OP10 AML in children: treatment approach in St. Jude

The prognosis for children with leukaemia has continued to improve over the past decade. The improved survival has, for the most part, not been caused by the introduction of new drugs. Instead, the improvement has resulted from a number of factors relevant to both acute lymphoblastic and acute myeloid leukaemia. Most important has been the progress made in the ability to assess prognosis using patient characteristics at diagnosis complemented by modern cytogenetic analysis of the leukaemic blasts. This has enabled patients to be allocated to appropriate treatment protocols, leading to an increased proportion of patients with a higher risk of relapse receiving more intensive chemotherapy. In addition, there has been a significant reduction in treatment-related mortality, mainly because of fewer infectious deaths, but also in part because of the lower rate of bone marrow transplantation seen in modern leukaemia protocols.

Effect of Age and Previous Autologous Transplantation on Nonrelapse Mortality and Survival in Patients Treated With Reduced-Intensity Conditioning and Allografting for Advanced Hematologic Malignancies

Older age and a previously failed autologous stem-cell transplantation (SCT) are poor prognostic factors for patients receiving myeloablative conditioning and allogeneic SCT. Reduced-intensity conditioning (RIC) regimens achieved a significant reduction of treatment-related mortality, but the influence of previously described risk factors on the outcome of this novel transplantation strategy have not been fully analyzed yet. One hundred fifty patients with advanced hematologic malignancies received a RIC regimen containing thiotepa (10 mg/kg), fludarabine (60 mg/m2), and cyclophosphamide (60 mg/kg), followed by an allogeneic transplantation from an HLA-identical sibling donor. Patients were divided into two cohorts according to age; 90 patients were younger than 55 years, and 60 patients were 55 years old or older. The other pretransplantation characteristics were fairly balanced. Actuarial 5-year nonrelapse mortality (NRM) rate was not statistically different between the groups (13% in the younger group and 19% in the older group). By univariate and multivariate analysis, NRM was significantly higher in older patients who previously experienced failure with an autograft. The occurrence of grade 3 to 4 acute graft-versus-host disease (GVHD) or extensive chronic GVHD was associated with a higher NRM in both age cohorts. Overall survival (OS) was not statistically different between the younger (66%) and older groups (61%). By multivariate analysis, refractory disease was associated with a worse OS irrespective of age group. RIC transplantations show a rather low NRM, and age > or = 55 years per se cannot be considered a risk factor anymore. The timing of transplantation and novel strategies for the prevention of severe GVHD could further improve patient outcome.

Effect of Age and Previous Autologous Transplant on Treatment-Related Mortality and GVHD in 140 Patients Treated with Reduce-Intensity Conditioning and Allograft for Advanced Hematological Malignancies.

Previous autografting and older age are traditionally considered poor prognostic factors for patients receiving myeloablative conditioning followed by allogeneic stem cell transplantation (SCT). Reduced intensity conditioning (RIC) achieved a significant reduction of treatment related mortality, but the influence of previously described risk factors on the outcome of this new strategy has not been fully described. We have evaluated if age older than 55 years and a failed autologous transplantation could have an impact on transplant-related mortality (TRM) and graft versus host disease (GVHD) occurrence. One hundred and forty allogeneic SCTs from HLA-identical sibling donors were analyzed: all patients received the same conditioning (Thiotepa 10mg/Kg, Fludarabine 60 mg/ms and Cyclophosphamide 60 mg/kg and) and GVHD prophylaxis (cyclosporin 2mg/kg and short course methotrexate). Patients were divided in two cohorts according to age: 86 patients were younger and 54 older than 55 years (range 20–69). Main pre-transplant characteristics were fairly well distributed in both cohorts, in terms of: sex, mismatch donor/recipient, CMV status, previous autografting, disease status at transplant, type of disease (lymphoid vs myeloid), stem cell source and number of previous lines of chemotherapy (<2 vs ≥2). Four-year treatment related mortality (TRM) was 13% for younger group and 17% for the older one (p=0.3), while overall survival (OS) was 58% and 59%, respectively (p=0.9). By univariate and multivariate analysis no pretransplant risk factor examined was found as significantly negative predictor of TRM; in particular no significantly association was found between a previously failed autograft and TRM in the younger (p=0.8) and in the older cohort (p=0.1). Instead, looking at GVHD, we observed that the occurrence of grade III–IV aGVHD was associated with a significantly worse TRM in both young (p=0.008) and elderly patients (p=0.005); similarly, extensive cGVHD was a predictor for worse TRM if compared to limited cGVHD in younger (p=0.8) and older patients (p=0.03). Finally, a strong association between favourable outcome and the onset of limited cGVHD was observed not only if compared to patients with extensive cGVHD but even compared to patients who never showed any sign of cGVHD; in fact 4-year OS curve for younger patients with limited cGVHD was 80% vs 50% of patients with no cGVHD (p=0.03); the same applies for the older cohort (4-years OS of 100% vs 48%, respectively). Our results indicate that: RIC can be safely applied to patients over 50 years; the deleterious effect of a previous failed autoBMT has been minimized by the RIC program. Moreover, severe GVHD still has a maior impact on the outcome; otherwise limited cGVHD seems an effective immunotherapy in high risk patients.

Preliminary Results of Sibling Donor Immunization with Patient-Derived Id-KLH Vaccine Prior to Reduced-Intensity Allogeneic Stem Cell Transplantation for Multiple Myeloma.

Reduced-intensity allogeneic stem cell transplantation (RIST) results in significant reduction in treatment-related mortality for multiple myeloma (MM) patients (pts); however, success with RIST is limited by a significant risk of relapse. To reduce the risk of relapse, HLA-matched sibling donors were vaccinated with patient-derived idiotype (Id) conjugated to keyhole limpet hemocyanin (Id-KLH) prior to stem cell donation with the goal of transferring tumor antigen-specific immunity. MM pts with HLA-matched siblings underwent plasmapheresis prior to treatment to generate Id-KLH vaccine. After vaccine generation donors received 3 SQ injections of Id-KLH + GM-CSF at 10, 8, and 4 weeks before G-CSF mobilized blood stem cell collection. During vaccine generation and donor immunizaton, MM pts received an induction regimen of EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine) to achieve a minimal disease state and deplete host T cells in preparation for RIST. MM pts then received a reduced-intensity conditioning regimen consisting of fludarabine (30 mg/m2/d x 4d) and cyclophosphamide (1200 mg/m2/d IV x 4d) followed by allogeneic stem cell infusion. MM pts were then vaccinated with the Id-KLH+GM-CSF at 3, 4, and 6 months post-RIST. Both donors and MM pts were monitored for Id-specific humoral and cellular responses. Five MM pts (ages: 50–60 years; IgG = 4, IgA = 1) and their respective donors have been enrolled onto study. Vaccine was generated from all 5 MM pts. All 5 donors completed vaccinations without significant complications; there were no grade 3 or 4 toxicities. Most common toxicities experienced by donors were erythema, pain, induration and pruritus at sites of injection and diffuse arthralgias. Four MM pts have undergone RIST. There has been one treatment-related death (GVHD) at day +67. Two patients are in CR at 15 and 9 months post-RIST; the third patient is in a PR at 4 months post-RIST. KLH-specific immunity was induced in all of the first 3 donors tested, and Id-specific T cell immunity was induced in 2 of the first 3 donors. In donor-MM pt pair #2 there was evidence that Id-specific T cell immunity was induced in the donor (Figure 1) and passively transferred to the recipient with RIST (Figure 2). Id-specific T cell responses were blocked with HLA Class I and Class II antibodies. These preliminary data confirm that Id-KLH vaccines can be safely and effectively given to normal stem cell donors. More importantly, these data suggest that tumor specific immunity can be induced and passively transferred to the recipient after RIST. Vaccination of donors with tumor-specific antigen represents a tactic to potentially reduce relapse after RIST. [Display omitted] [Display omitted]

Impact of Surgery, Chemotherapy and Irradiation on Long Term Outcome of Intracranial Malignant Non-Germinomatous Germ Cell Tumors: Results of the German Cooperative Trial MAKEI 89

Malignant non-germinomatous intracranial germ cell tumors (MNGGCTs) are a heterogenous group of neoplastic lesions. Their treatment concept follows a multimodal concept that may include tumor resection for local tumor control, craniospinal irradiation to cover leptomenigeal tumor spread and chemotherapy to eliminate systemic tumor dissemination. A Platinum-based chemotherapy proven to be highly effective in testicular and non-testicular malignant germ cell tumors in adults as well as in children has also been chosen for intracranial sites. While therapeutic concepts have been thoroughly evaluated for children and adolescents with extracranial nongonadal GCTs, no such detailed long term follow-up data are available for intracranial MNGGCTs. This paper reports on the long-term outcome of 41 patients with intracranial malignant non-germinomatous GCTs enrolled into the German prospective protocol MAKEI 89. The analysis focuses on the impact of surgery, radio- and chemotherapy. Between January 1989 and January 1994, 41 patients with malignant intracranial non-germinomatous GCTs were registered. Patients were compared in respect to protocol (n = 27) and non-protocol treatment (n = 14). Estimated were with chi (2) and Fisher exact test the impact of surgery, chemotherapy and irradiation on outcome. The estimated (Kaplan-Meier) 5-year event free survival (EFS) of patients treated according to protocol recommendations was 0.59 +/- 0.06 (n = 27), compared to an EFS of 0.37 +/- 0.33 for patients with different treatments (n = 14) (p = 0.70, log-rank). The 5-year relapse-free survival rate (RFS) was 0.74 +/- 0.06 in protocol patients and 0.38 +/- 0.33 in non-protocol patients (median observation time of 112 months after diagnosis for surviving patients) (p = 0.14, log-rank). Surgery, complete or incomplete had no significant impact on survival (p = 0.12). Radiotherapy, in terms of craniospinal irradiation had a significant influence on survival (p = 0.035) as well as a cumulative cisplatin dose >/= 400 mg/m (2) (p = 0.002). Cisplatin chemotherapy and craniospinal irradiation with tumor boost are of significant influence on long term survival in patients with MNGGCTs. The exclusion of major surgery at diagnosis using modern advances in neurosurgery or related tumor resection after neoadjuvant chemotherapy will allow a further reduction of treatment related mortality and long lasting morbidity. The analysis reveals that, given effective treatment, intracranial malignant non-germinomatous GCTs should not longer carry a poor prognosis.

Adoptive immunotherapy with antigen-specific T cells in myeloma: a model of tumor-specific donor lymphocyte infusion

Although partial remissions rates of up to 60% are obtained with conventional therapeutic regimens, multiple myeloma is essentially an incurable disease with a median survival of approximately 30 months. Allogeneic stem cell transplantation (SCT) results in a high percentage of complete remissions (CRs), but it can be associated with significant treatment-related mortality. Recent clinical studies have shown that highly immunosuppressive, yet nonmyeloablative, doses of fludarabine-based chemotherapy can result in alloengraftment. However, even with a reduction in treatment-related mortality, success with allogeneic SCT is limited by the significant risk of relapse. The goal of the strategy described is to transfer tumor antigen-specific immunity induced in the stem cell donor to the allogeneic SCT recipient to reduce relapse. Donors are immunized with a well-defined vaccine, specific for the patient’s tumor. The allogeneic SCT is performed with a conditioning regimen consisting of cyclophosphamide and fludarabine, and the stem cell source is blood mobilized with filgrastim, which could potentially enhance the transfer of a larger number of tumor-specific T cells in the allograft, as compared to bone marrow. Donor immunization with myeloma idiotype protein in the setting of a nonmyeloablative SCT may represent a novel strategy for the treatment of myeloma.

The Allogeneic Effect in Non-Hodgkin's Lymphoma

Allogeneic hematopoietic stem cell transplantation (HSCT) has been restricted to medically fit patients under the age of 55 years due to adverse effects of the intensive conditioning regimens. Autologous HSCT has not proven to be a particularly effective treatment for patients with low-grade non-Hodgkin's lymphoma (NHL). Much of the benefit of allogeneic HSCT appears to be mediated by a graft-vs.-tumor (GVT) effect. Reduced-intensity regimens in allogeneic HSCT have been developed to minimize conditioning regimen-related toxicities and to control the malignancy until a GVT effect is established. A number of studies investigating reduced-intensity allogeneic HSCT are discussed. Results from these studies suggest that indications for allogeneic transplant include patients with low-grade NHL with a sibling or matched donor who are under 60 years of age; young patients with mantle cell lymphoma who are in first remission and have a sibling or matched donor; patients with high-grade NHL who have already failed an autograft but have chemosensitive disease, and those under 30 years of age who have poor-risk disease and are in first remission. It is concluded that reduction in treatment-related mortality with reduced-intensity HSCT and the presence of GVT effects increases the applicability of allogeneic transplantation for NHL. However, treatment will be improved by optimizating conditioning regimens and a better understanding of patient selection criteria and the immune processes involved in graft-vs.-host disease and GVT.

Recent advances in the management of leukaemia

The prognosis for children with leukaemia has continued to improve over the past decade. The improved survival has, for the most part, not been caused by the introduction of new drugs. Instead, the improvement has resulted from a number of factors relevant to both acute lymphoblastic and acute myeloid leukaemia. Most important has been the progress made in the ability to assess prognosis using patient characteristics at diagnosis complemented by modern cytogenetic analysis of the leukaemic blasts. This has enabled patients to be allocated to appropriate treatment protocols, leading to an increased proportion of patients with a higher risk of relapse receiving more intensive chemotherapy. In addition, there has been a significant reduction in treatment-related mortality, mainly because of fewer infectious deaths, but also in part because of the lower rate of bone marrow transplantation seen in modern leukaemia protocols.

Recent advances in the treatment of multiple myeloma.

Multiple myeloma represents the second most common hematologic malignancy, with nearly 15,000 new cases each year in the United States. Although further understanding of the pathogenesis of this B-cell malignancy has been made, the disease remains incurable with a median survival of approximately 3 years. The identification of new genetic events in the malignant cells themselves may lead to new potential therapies. Moreover, recent identification of the new human herpesvirus 8 in the supporting cells of the bone marrow of these patients will likely change approaches to this disease in the laboratory and the clinic. Further development of new high-dose therapy approaches has led to a reduction in treatment-related mortality with an improvement in overall survival. Treatment with the bisphosphonate pamidronate reduces skeletal complications and may also improve overall survival of these patients.