High Incidence Of Treatment-related Mortality Research Articles

Promising survival rate but high incidence of treatment-related mortality after reduced-dose craniospinal radiotherapy and tandem high-dose chemotherapy in patients with high-risk medulloblastoma.

BackgroundIn this study, we report the follow‐up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high‐dose chemotherapy (HDCT) in patients with high‐risk medulloblastoma (MB).MethodsNewly diagnosed high‐risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2, or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre‐RT chemotherapy, radiotherapy (RT) including reduced‐dose CSRT (23.4 or 30.6 Gy), four cycles of post‐RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues.ResultsIn all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5‐year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment‐related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Taken together, the 5‐year event‐free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high‐tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.ConclusionsThe strategy using tandem HDCT following reduced‐dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study.

A Reduced-Intensity Conditioning Regimen for Patients with Dyskeratosis Congenita Undergoing Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for progressive marrow failure, myelodysplastic syndrome, or leukemia associated with dyskeratosis congenita (DC). HSCT for DC is limited by a high incidence of treatment-related mortality, thought to be related to underlying chromosomal instability and sensitivity to chemotherapy and radiation. We report our experience in 7 patients with DC who underwent allogeneic transplantation using a reduced-intensity conditioning (RIC) preparative regimen that contained chemotherapy only (no radiation). This RIC regimen, designed specifically for patients with DC, contained alemtuzumab, fludarabine, and melphalan (with melphalan at 50% reduced dosing), with the goal of decreasing toxicity and improving outcome. All 7 patients engrafted, with none developing mixed chimerism or rejection. Two patients experienced acute graft-versus-host disease (GVHD) and 1 went on to develop limited chronic GVHD of the skin. Five patients remain alive and well at a median follow-up of 44 months (range, 14 to 57 months). We conclude that a radiation-free RIC regimen results in durable engraftment, acceptable toxicity, and improved overall survival in patients with DC undergoing allogeneic HSCT.

Gemtuzumab Ozogamicin Reduces Relapse Risk in FLT3-ITD+ Acute Myeloid Leukemia: A Report from the Children’s Oncology Group

CD33 is variably expressed on most acute myeloid leukemia (AML) blasts and is the target of gemtuzumab ozogamicin (GO), a calicheamicin-conjugated anti-CD33 monoclonal antibody. COG studies AAML03P1 and AAML0531 evaluated the safety and efficacy of GO combined with conventional chemotherapy to determine the impact of GO on treatment outcomes. We have previously demonstrated that those with high CD33 expression are more susceptible to GO. As FLT3-ITD is associated with high levels of CD33 expression, this group of patients represents a subgroup of particular interest for this therapeutic approach. Patients with high-allelic ratio (HAR) FLT3-ITD have poor outcomes with conventional chemotherapy alone and experience improvement with allogeneic hematopoietic stem cell transplant (HCT). Thus, COG AAML0531 allocated HAR FLT3-ITD+ patients enrolled after April 14, 2008 to consolidation allogeneic HCT with the best available donor.In combined evaluation of COG AAML0531 and its preceding pilot study AAML03P1, 479 patients received conventional MRC based induction chemotherapy (0531 Arm A) and 735 patients received conventional chemotherapy + GO (03P1 and 0531 Arm B). A total of 183 FLT3-ITD+ patients were treated on 0531 Arm A (n=71) and on 03P1/0531 Arm B (n=112). Overall, patients with FLT3-ITD had significantly lower rates of complete remission (CR) compared to FLT3-ITD negative patients, 64% v. 77% respectively (p<0.001). Among FLT3-ITD+ patients, CR rates were identical in those with or without induction GO exposure of 64% vs. 64% respectively (p=0.98).Analysis of 5-year outcomes for FLT3-ITD+ patients treated with GO compared to no GO demonstrated no difference in overall survival (OS) (50% v 49% respectively, p=0.74). Importantly, cumulative incidence of relapse (CIR) at 5 years from CR for patients treated with GO was 37% vs. 59% in those who did not receive GO (p=0.018). This GO-associated improvement in relapse was offset by higher treatment related mortality (TRM) among GO compared to no GO recipients (16% v 0% respectively, p=0.008), leading to similar DFS of 47% vs. 41% respectively (p=0.45). The benefit of decreased relpase risk (RR) was most significant for patients receiving GO in addition to HCT. Among FLT3-ITD+ patients who underwent HCT, those who received GO (n=33) had a 5-yr RR of 22% compared to 56% for the no GO cohort (n=25, p=0.003). There was a trend towards increased TRM among patients receiving GO compared to no GO (22% v. 4% respectively, p=0.078), with a corresponding DFS in GO recipients of 56% vs. 40% for the no GO cohort (p=0.09). Evaluation of the 8 GO recipients who died at HCT revealed that 3 (38%) were the result of complications from transplant-associated sinusoidal obstructive syndrome.Patients with HAR FLT3-ITD, who experience poor outcomes with conventional chemotherapy alone, were analyzed separately to evaluate the impact of induction GO on outcomes. Among HAR FLT3-ITD+ patients who underwent HCT, those treated with GO (n=26) had a significantly lower RR of 15% compared to 53% among no GO recipients (n=15, p=0.007). Additionally, patients receiving GO had a trend towards higher DFS of 65% compared to 40% for no GO group, (p=0.079). In this cohort, TRM in GO vs. no GO recipients was 19% vs. 7% respectively (p=0.297). Among HAR FLT3-ITD+ patients who did not receive HCT, there were no significant differences in DFS, RR, and TRM among the GO versus no GO recipients.Data from the two consecutive COG studies AAML03P1 and AAML0531 suggest that FLT3-ITD+ patients may benefit from the addition of GO to intensive chemotherapy. There is further evidence that HCT may augment the therapeutic impact of induction GO by further reducing the risk of relapse. However, clinical impact of GO was tempered by higher incidence of TRM in GO recipients. CD33 targeting represents an attractive approach in FLT3-ITD+ patients as they often have elevated blast CD33 expression. Further understanding of the toxicity profile of GO, especially when used in conjunction with intensive chemotherapy and HCT, is needed to enhance its therapeutic benefit. Additionally, its impact may be most significant in certain biologic subsets of AML. Our findings demonstrate that CD33 targeting is an important treatment strategy in AML that warrants further investigation in FLT3-ITD+ patients. DisclosuresNo relevant conflicts of interest to declare.

Allo-SCT for multiple myeloma: a review of outcomes at a single transplant center

Allogeneic stem cell transplant for multiple myeloma (MM) is one treatment associated with long-term disease-free survival. The high incidence of treatment-related mortality and relapses, however, are important reasons for controversy about the role of allografting in the management of MM. We reviewed our results of allografting for MM spanning a period of 34 years in order to better define long-term outcomes and identify areas of progress as well as areas requiring improvement. A total of 278 patients received allogeneic marrow or PBSCs after high-dose myeloablative (N=144) or reduced intensity, non-myeloablative (N=134) regimens. In multivariable analysis, adjusting for differences in patient groups, reduced intensity/non-myeloablative transplants were associated with significantly less acute GVHD, lower transplant mortality, better PFS and overall survival. There were no significant differences in relapse, progression or chronic GVHD, when adjusted. In multivariable analysis of patients receiving only non-myeloablative transplants, decreased overall survival and PFS were associated with relapse after a prior autograft and a β2 microglobulin >4.0. Transplant mortality was reduced and only influenced by a prior tandem autograft.

Frontline treatment of follicular lymphoma with fludarabine, cyclophosphamide, and rituximab followed by rituximab maintenance: toxicities overcome its high antilymphoma effect. Results from a Spanish Cooperative Trial (LNHF-03)

We assessed the efficacy of fludarabine, cyclophosphamide, and rituximab in combination (FCR) as frontline treatment in patients with follicular lymphoma (FL) followed by rituximab maintenance. Seventy-five untreated patients with FL received FCR followed by maintenance with rituximab 375 mg/m2 weekly during 4 weeks and every 6 months for 2 years. The overall response rate was 100%, with 89% complete remission (CR) and 11% partial remission (PR). Molecular remission was observed in all but one patient. Only eight patients completed all therapy planned. With a median follow-up of 47 months, the 5-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were 77%, 93%, and 72%, respectively. Age below 60 and low Follicular Lymphoma International Prognostic Index (FLIPI) correlated with a better EFS. Ten patients died due to toxic complications. The FCR regimen is highly effective in untreated patients with FL, with 89% CR, including molecular responses, and a low progression rate. However, the high incidence of treatment-related mortality makes this regimen unsafe and it cannot be recommended as an upfront therapy in FL.

Allogeneic Stem Cell Transplantation (Allo-SCT) in Adults with Acute Myelogenous Leukemia (AML). Final Analysis of JALSG AML97 Study

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is considered to be the most intensive post remission treatment consisting of high-dose chemoradiotherapy and allo-immune mechanisms. However, the powerful anti-leukemic effects of this treatment are counterbalanced by a high incidence of treatment-related mortality (TRM), thus allo- SCT has not always been considered superior to chemotherapy. The aim of this study was to investigate the efficacy of allo-SCT as a postremission treatment in patients with intermediate/poor risk AML in first CR. Previously untreated patients aged 15 – 50 years were eligible. Patients received standard induction therapy consisting of cytarabine (100 mg/ m2 d1–7) and idarubicin (12 mg/m2 d1- 3). If the patients did not achieve remission after the first induction therapy, then the same induction therapy was given again. The patients who achieved CR were randomized into an intensified short-course postremission chemotherapy group (arm A) or conventional JALSG postremission chemotherapy group (arm B). Patients were also categorized into good, intermediate or poor risk groups by risk factors selected from previous JALSG AML trials using univariate and multivariate analyses. Intermediate or poor risk patients with living siblings were tissue typed. If an HLA matched sibling was found it was assumed that the patient would receive allo-SCT during CR1 (donor group). Those without living or HLA matched siblings were assigned to the no-donor group that continued receiving chemotherapy. The disease-free survival (DFS) rates, the relapse incidence rates (RI), TRM and the overall survival (OS) rates of the patients of the donor group were compared with those of the no-donor group on the basis of the intention to treat.Result: Of 503 patients aged 15 – 50 years old registered between December 1997 and July 2001, 397 achieved complete remission (CR). The 5-year OS rate of the CR patients with good, intermediate and poor risk was 68%, 43% and 29%, respectively (p<0.001), showing successful stratification by the JALSG scoring system. Among those who achieved CR with intermediate or poor risk, 75 with and 95 without an HLA matched sibling were assigned to the donor and no-donor groups, respectively. The actual risk of relapse at 8 years was significantly lower in the donor group than in the no-donor group (54% versus 78%, p=0.009). The TRM did not significantly differ between the donor group and the no-donor group (16% versus 17%, p= 0.948). The lower relapse rate in the donor group resulted in a significantly better DFS compared with the no-donor group (38% versus 18%, p=0.017). The significant superiority of DFS in the donor group was translated into a higher OS rate, however, the difference in OS between the two groups did not reach statistical significance (45% versus 28%, p=0.089). The OS of the patients younger than 35 years of age were comparable between the donor group and the no-donor group. However, the OS in the donor group patients older than 36 years old was significantly better than the other (47% versus 23%, p= 0.032).Conclusions: Our study showed that allo-SCT reduced the risk of relapse and contributed to the survival advantage of AML patients aged from 36 to 50 years old with intermediate or poor risk.

Elevated Ferritin Is Associated with Poorer Survival Following Nonablative Allogeneic Transplantation.

Iron overload is a well-established adverse prognostic factor for allogeneic hematopoietic stem-cell transplantation in thalassemia and appears to adversely affect prognosis with myeloablative transplantation for other diseases as well. In thalassemia, modification of the preparative regimen improves prognosis in patients who are at high risk due to iron overload. We analyzed a large group of patients who received a nonablative preparative regimen for allogeneic transplantation to determine whether the adverse impact of iron overload was circumvented by nonablative transplantation. Sixty-four consecutive patients undergoing nonablative allogeneic transplantation between 12/00 and 12/06 had pretransplant ferritin levels within 100 days preceding transplantation. Median age was 57 (range, 24–67) years; 24 patients were female. Median interval from diagnosis to transplant was 14.5 months (range, 2.4 to 151.6). Diseases included AML (n=16), NHL (15), MDS (10), myelofibrosis (6), CLL (6), CML (5), MM (3), Hodgkin (2), and ALL (1). Six had undergone prior transplantation. Median ferritin was 961 ng/mL (range, 302–6251). All but two received Flu/TBI preparation. Thirty-nine were sibling and 25 unrelated donors. Recursive partitioning identified significantly better survival for patients with ferritin ≤ 1615 ng/mL (n=45) compared to those with ferritin >1615 ng/mL (n=19; P=.012) as shown: [Display omitted] Among age, gender, diagnosis, interval from diagnosis to transplant, extent of therapy prior to transplant, ferritin level, albumin, AST, alkaline phosphatase, bilirubin, LDH, risk group, donor source, degree of HLA match, donor to recipient gender, and CD34+ dose, only ferritin >1615ng/ml (P=.010, HR= 2.74), older age (P=.049, HR= 1.63), and prior transplantation (p=.002, HR=5.78) were adverse prognostic factors for survival in multivariable analysis. The poorer survival was related to both a higher incidence of treatment-related mortality and a higher rate of relapse mortality, neither of which reached statistical significance. The addition of albumin, a negative acute phase reactant, did not change the prognostic impact of ferritin.Conclusion: Similar to patients who undergo myeloablative transplantation, survival of patients who undergo nonablative allogeneic transplantation is adversely affected by elevated ferritin. It is important to assess the influence of specific factors on comparative results of myeloablative and nonablative transplantation. These results should stimulate study of iron chelation prior to allogeneic transplantations.

Allogeneic myeloablative transplantation for patients aged 50 years and over.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed mainly for young patients due to concern about the high incidence of treatment-related mortality (TRM). Recent advances to reduce TRM by using peripheral blood stem cells or nonmyeloablative conditioning regimens have increased the age limit for this procedure, and correctly identifying the indication for transplant is essential for older patients. In this study, we analyzed data from 398 patients aged 50 or over selected from 5147 patients, who received conventional allogeneic HSCT (c-HSCT). Patients aged 50 or older showed inferior outcomes for TRM and overall survival (OS). Mulitivariate analyses confirmed that an age of 50 or over was an independent risk factor for TRM (P<0.0001) and OS (P<0.0001). Among patients aged 50 or older, increasing age remained an adverse factor for OS (P=0.0213). Regimens including total-body irradiation (TBI) correlated with a higher risk of TRM and a lower OS for older patients (P=0.0095 and 0.0303, respectively). These findings indicate that allogeneic c-HSCT should be offered to patients over 50 years only if the increased risk of TRM is acceptable, and that a non-TBI regimen is preferable when the transplant is performed.