To Treatment-related Mortality Research Articles

Allogeneic stem cell transplantation in patients with multiple myeloma-single center experience.

The standard of care in multiple myeloma (MM) consists of induction chemotherapy followed by autologous stem cell transplant (autoSCT), but this setting doesn't present curative potential. Despite advances in new, efficient, and targeted drugs, allogeneic transplant (aloSCT) remains the modality with curative potential in MM. With the knowledge of high mortality and morbidity related to the treatment in comparison to treatment with novel drugs, there is no consensus in the indication of aloSCT in MM, also the choice of ideal patients profiting from this method is difficult. Therefore, we performed a retrospective unicentric study of 36 unselected consecutive patients transplanted for MM in the University Hospital in Pilsen between the years 2000-2020 in order to define possible variables influencing survival. The median age of the patients was 52 years (38-63) and the distribution of MM subtypes was standard. The majority of the patients were transplanted in the relapse setting, 3 (8.3%) patients in the 1st line setting, and in 7 (19%) patients elective auto-alo tandem transplant was performed. 18 patients (60% of patients with available cytogenetics (CG) had high-risk disease. 12 (33.3%) patients were transplanted with chemoresistant disease (at least PR not reached). With a median follow-up of 85 months, we observed median overall survival (OS) of 30 months (range 10-60) and median progression-free survival (PFS) of 15 months (11-175). 1- and 5-year Kaplan Meier survival probabilities for OS were 55% and 30.5% respectively. During the follow-up, 27 (75%) patients died, 11 (35%) due to treatment-related mortality (TRM), and 16 patients (44%) due to a relapse. 9 (25%) patients were still alive, 3 (8.3%) of them with complete remission (CR), and 6 (16.7%) patients with relapse/progression. Altogether 21 (58%) of the patients relapsed/progressed with a median of 11 months (3-175). Incidence of clinically significant acute graft versus host disease (aGvHD gr. >II) was low (8.3%) and extensive chronic GvHD (cGvHD) developed in 4 patients (11.1%). Univariant analysis proved marginal statistical significance in disease status before aloSCT (chemosensitive × chemoresistant) for OS, favoring patients with the chemosensitive disease (HR 0.43, 95% CI 0.18-1.01, p=0.05), there was no significant impact of high-risk cytogenetics (CG) on survival. No other analyzed parameter was found to be significant. Our findings support the conclusion that aloSCT is able to overcome high-risk CG and that aloSCT still remains a valid treatment choice with acceptable toxicity in well-selected high-risk patients with curative potential, even though often with active disease, but not derogating the quality of life significantly.

Reduced Intensity Reinduction Followed By Blinatumomab Achieves Excellent MRD Clearance with Reduced Toxicity and Facilitates Timely Transplant in Children and Young People with Relapsed B-Precursor Acute Lymphoblastic Leukemia

Introduction Despite the emergence of effective novel immunotherapies, the outcome of relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains poor due to treatment-related mortality (TRM) and resistant disease. In response to accumulating evidence on the efficacy and low toxicity of blinatumomab in relapsed B-ALL and the availability of highly active CD19-targeted chimeric antigen receptor T-cell therapy (CART), we redesigned the United Kingdom (UK) relapse treatment pathway, based on two key guiding principles: 1) to reduce chemotherapy burden and associated toxicity through a move away from the highly intensive ALL R3 backbone towards increased reliance on blinatumomab to clear disease, and 2) to identify treatment failures early and direct them to CART, given the poor responses reported with hematopoietic stem cell transplant (HSCT) in this context. Methods Patients were treated with UKALL induction chemotherapy (<16yr: 3-drugs; >16yr: 4-drugs) until adequate blast clearance. Patients with blasts <5% at Day 15 progressed directly to blinatumomab; remaining patients continued to Day 28. Following reinduction, patients received up to 2 cycles of blinatumomab as a single agent. HR patients (early/very early relapses and/or HR cytogenetics) proceeded to HSCT once minimal residual disease (MRD) <0.01%. Those with high-risk (HR) isolated central nervous system (CNS) disease had the option to proceed directly to HSCT following CSF blast clearance without blinatumomab. All Standard risk (SR) patients continued on chemotherapy alone. Patients who were refractory after re-induction (>25% disease), blinatumomab (MRD >0.01%), or for whom there was no available donor were considered for CART. All patients were required to be discussed at a national tumour board, and data were subsequently collected every 3 months for analysis. Events were defined as death, relapse, and secondary cancer. Results Between September 2018 and July 2022, 111 patients were treated on the pathway; 63 (56.8%) were HR and 48 (43.2%) were SR. There were 26 patients >15yr, 3 Infant ALL, 2 Ph+ ALL and 4 with Down Syndrome. Induction therapy achieved disease reduction to <5% and CNS clearance in 98 patients (88%). Of the 90 patients with BM involvement, 52.2% required only 15 days of induction therapy. Induction failure (>25% blasts) occurred in 6.3%, comparable to the 7.1% using the R3 induction in the COG AALL1331 trial (p=1.00); 6/7 patients with induction failure successfully underwent CART infusion. The rate of end of induction MRD <0.01% in the HR group was also similar to COG AALL1331 (30% vs. 27.4%, p=0.669). Importantly, there were no cases of TRM with the reduced intensity induction, compared to 2.4-4% reported with the ALL R3 induction (p=0.06). Ninety patients received blinatumomab, of whom 87% achieved a complete MRD response, with grade 3 or 4 treatment-related toxicity in 11 patients (12.2%). Amongst HR patients, 86.8% underwent HSCT, significantly more than in the blinatumomab-treated IR/HR arm of COG AALL1331 (66%, p=0.02). With a median follow-up of 12 months (range 2-49), 19% of HR patients and 8.3% of SR patients have relapsed, comparable to results achieved in the blinatumomab-treated arm of the COG AALL1331 trial. There were no deaths in the SR group, and 12 deaths in the HR group (6 due to relapse/refractory disease, 6 due to post-HSCT TRM). Conclusions Our findings demonstrate that a reduced intensity reinduction can achieve equivalent disease control to the more intensive ALL R3 induction, with a substantial reduction in TRM. Although follow-up is short, consolidative blinatumomab achieved very high rates of MRD clearance, allowing a greater number of HR patients to reach potentially curative therapy with HSCT, the key predictor of outcome in the COG AALL1331 trial. We propose that our strategy represents a new standard of care for reinduction therapy in relapsed childhood B-ALL. DO and AV are joint senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium

Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium

DONOR CHIMERISM IN PATIENTS WITH PRIMARY IMMUNODEFICIENCY AFTER ALLOGENEIC HEMATOPOIETIC STEM CELLS TRANSPLANTATION

Allogeneic stem cell transplantation (alloHSCT) is effective curative option for a broad range of primary immunodeficiencies (PIDs). Hematopoietic chimerism monitoring in patients with various PIDs and its connection with the outcome of alloHSCT is of great interest. In this study 16 alloHSCT in patients with PIDs were included. Three-year overall survival was 72.2 ± 12.0 %. Full donor chimerism (FDC) was achieved in 13 (81.25 %) patients. Prolonged persistence of mixed chimerism (MC) was observed in 3 (18.75 %) patients. In patients with MC in the peripheral blood, circulating T-cells are completely or predominantly of donor origin, whereas granulocytes are predominantly or completely recipient cells, and chimerism in B-cells differs significantly from 0 % chimerism to FDC. In patients with PIDs, engraftment of individual cell lines (split chimerism) could be observed. In some patients chimerism decreased during the first year after alloHSCT with its subsequent stabilization. Increasing MC is not associated with transplant rejection in PIDs. FDC in patients with PIDs provides restoration of all cell lines participating in the immune response regardless of the diagnosis, but it is associated with more frequent development of «graft-versus-host» disease (GVHD), which is a serious complication of alloHSCT and can lead to treatment-related mortality (TRM). MC/split chimerism, in which the frequency of development of GVHD is less, can also provide the formation of a full immune response and correction of other disease manifestations, but only when replacing defective cell lines according to the diagnosis.

Evaluation of treatment-related mortality among paediatric cancer deaths: a population based analysis

Background:Objectives were to describe the proportion of deaths due to treatment-related mortality (TRM) and to identify risk factors and probable causes of TRM among paediatric cancer deaths in a population-based cohort.Methods:We included children with cancer ⩽18 years diagnosed and treated in Ontario who died between January 2003 and December 2012. Deaths were identified using a provincial registry, the Pediatric Oncology Group of Ontario Networked Information System. Probable causes of TRM were described.Results:Among the 964 deaths identified, 821 were included. The median age at diagnosis was 6.6 years (range 0–18.8) and 51.8% had at least one relapse. Of the deaths examined, TRM occurred in 217/821 (26.4%) while 604/821 (73.6%) were due to progressive cancer. Deaths from TRM did not change over time. Using multiple regression, younger age, leukaemia diagnosis and absence of relapse were independently positively associated with TRM. The most common probable causes of TRM were respiratory, infection and haemorrhage.Conclusions:TRM was responsible for 26.4% of deaths in paediatric cancer. Underlying diagnosis, younger age and absence of relapse were associated with TRM and causes of TRM differed by diagnosis group. Future work should evaluate TRM rate and risk factors among newly diagnosed cancer patients.

Child and adolescent Down syndrome-associated leukaemia: the Irish experience.

Down syndrome (DS), the most common syndromic chromosomal abnormality is associated with a unique susceptibility to develop both acute myeloid (ML) and lymphoblastic leukaemia (ALL). These leukaemias differ from the non-DS-related types of leukaemia and are thought to be distinct biological entities. To perform a retrospective review of our experience of treating DS-related leukaemia at Our Lady's Children's Hospital. Data were extracted from a database established in 2000 to prospectively gather data on DS-associated leukaemias and their outcomes following polychemotherapy. Kaplan-Meier survival curves were constructed. Nineteen patients with DS-ML were treated and 19 with DS-ALL. Sixteen (84%) patients with DS-ML are alive and in complete remission with a median follow-up of 7 years. All deaths in this cohort were due to treatment-related mortality (TRM). Of the DS-ALL patients, 12 (63%) remain alive with a median follow-up of 3.6 years. TRM accounted for five of the six deaths. One death was due to leukaemic relapse. High cure rates are seen in DS-ML using contemporary polychemotherapy protocols, however, there is significant TRM in this cohort. DS-ALL does not have the same high cure rate as non-DS-ALL (>90%) and again this is mainly due to an excess of TRM.

Pre-Engraftment Syndrome After Myeloablative Umbilical Cord Blood Transplantation: Risk Factors and How To Stratify

IntroductionPre-engraftment syndrome (PES) is a group of symptoms occurred after hematopoietic stem cell transplantation especially unrelated cord blood transplantation(UCBT) before the engraftment, including unexplained fever higher than 38.3°CAunexplained erythematous skin rashAdiarrheaAhepatic dysfunction Anon-cardiogenic edemaApulmonary infiltrates and weight gain. Severe PES can be fatal, however there's no criteria to define it. We retrospectively analyzed the incidence, risk factors, manifestations and clinical outcomes of PES in CBT recipients, who had been treated for hematologic malignancies. All patients received TBI(12GY)/Ara-c(8g/ m2)/CY(120mg/kg) without ATG or Flu(120mg/ m2)/Ara-c(8g/ m2)+BU(12.8mg/kg)+CY (120mg/kg) myeloablative conditioning. MethodsFrom April 2010 to July 2011, 61 patients underwent UCBT at our transplantation center and 40 patients(65.6%) developed PES at a median of 7 d (range 5–13) post-transplant. We analyze 8 factors related to treatment-related mortality (TRM) within 180 days : occurrence timeAthe maximum temperatureAclinical symptomsAconcentration of CyclosporinAthe initial dose of MPAmethylprednisolone (MP) effective daysAdays till MP reduced and reoccurrence after symptoms under control. Univariate analysis identified early occurrence time( day +5 or +6 ) AMP effective days and clinical symptoms as significant risk factors for higher TRM. In a multivariate analysis, we found these three factors are independent and have no interactions. We retrospectively analyze all the patients who developed PES from April 2010 to December 2012. ResultsThere were 94 cases and we scored them based on these three factors. The patient got one score for each factor if he/she got a fever on day 5-6 after UCBT or had more than two clinical symptoms or not under control after 7 days of MP. We added the three scores together and divide the patients into four groups according to the total score(zero for Group 1Aone score for Group 2Atwo score for Group 3Athree for Group 4). The number of patients for Group 1-4 was 32A32A18 and 12. There is a significant difference for the TRM within 180 days between Group 4(58%) and Group 1(18.7%)AGroup 2(22.2%) (P<0.01). The TRM of Group 4 in one year is 66.7%, which is significantly higher than Group 1( 22.7%), Group 3(22.2%) (P<0.01), but shows less significant difference compared with TRM of group 2, which is 33%. The relapse rate of one year for each group from 1 to 4 was 9%A16.7%A5.5%A8.3%. The probability of one-year disease-free survival (DFS) was much higher in Group 1 (71.7%) and 3(72.2%) than Group 4(25%) (P<0.01). The difference was apparent as to the probability of one-year overall survival (OS) between Group 1 (74.8%) and 4(25%), the same is true whith Group 3 (71.3%) and 4(25%). The difference between Group 2(55.4%) and Group 4 was not clearly significant (P=0.06). ConclusionsRecognizing and treating immediately severe PES will significantly reduce the TRM of UCBT. Our analyze confirmed that these three factors are crucial to define severe PES .We therefore put forward this ranking method to help to diagnosis and take effective treatment. Disclosures:No relevant conflicts of interest to declare.

How Can Outcomes Be Improved for Older Patients With Hodgkin Lymphoma?

Older age has consistently been identified as an independent adverse prognostic factor for Hodgkin lymphoma (HL) survival in population-based studies and clinical trials in the last several decades. In the 1970s and 1980s, 5-year event-free survival or freedom from treatment failure rates for older (or elderly) patients with HL, most commonly defined as age 60 years, ranged from 30% to 40% with 5-year overall survival (OS) rates of 40% to 50%. These rates are markedly inferior compared with patients with HL younger than age 60 years with 5-year event-free survival of 70% to 75% and OS greater than 80% to 85%. An important question is: have outcomes improved for older patients with HL with refined therapeutic regimens and enhanced supportive care measures in the contemporary era? In a 2008 SEER database analysis, Brenner et al reported improved HL survival over time across all age groups, including older patients. The 5-year survival rates for patients age 60 years increased from 1980 to 1984 through 2000 to 2004 (35% to 59%, respectively). However, the survival rates were exceptionally low from 1980 to 1984, and they still remained significantly lower ( 30% to 35%) in the latter time period compared with younger populations. Recent prospective data in advanced-stage HL confirmed this. Outcomes for patients with HL age 60 years on the phase III study E2496 (treated with ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] or Stanford V) seemed improved with historical controls but remained much lower compared with patients younger than age 60 years (5-year failure-free survival [FFS] and OS: 48% and 58%, respectively, v 74% and 90%, respectively). Notably, these survival disparities cannot be explained merely by the advanced age of patients. In a recent retrospective analysis of older patients with HL treated in the current era, we reported 5-year progression-free survival (PFS) and OS of 44% and 58%, respectively, which were significantly inferior compared with an ageand sex-matched population (Fig 1). The cause of poor outcomes for older patients with HL is likely multifactorial, including presence of comorbidities and decreased organ reserve leading to increased toxicity and poor tolerability of therapy, which compromises chemotherapy dose-intensity and contributes to treatment-related mortality (TRM). BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in the “baseline” form has been shown to be too toxic with a reported TRM rate of 21% in patients with HL age 66 to 75 years. Many bleomycin-containing regimens, including ABVD, are poorly tolerated; this is partly from the risk of the potentially lethal adverse event, bleomycin lung toxicity (BLT). The incidence of BLT in the literature is variable, including up to 46%. Older age is a well-described risk factor associated with BLT in addition to cumulative bleomycin dose, renal insufficiency, pulmonary radiation, and high fractions of inspired oxygen. The incidence of BLT in our Chicago series of patients with HL age 60 years was 32% with an associated mortality rate of 25%. Furthermore, the rate of BLT was much higher in patients who received granulocytestimulating growth factor versus those who did not (ie, 38% v 0%, respectively; P .001), which supports prior data suggesting granulocyte-stimulating growth factor increases the risk of BLT. Several sources of evidence have also suggested that HL in older 0 HL population General US population Ov er al l S ur vi va l ( % )

Pretherapy and posttherapy 18F-FDG PET/CT in isolated nasoseptal diffuse large B-cell lymphoma

The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatment-related mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on OS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell–replete allografts from HLA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy (P = .0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor (P < .0001) relative to OS, and there was a trend (P = .056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT.

Early Mortality After Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies Performed In the Recent Era

AbstractAbstract 902 Background:HCT is a curative option for patients with hematologic malignancies. However, the procedure carries a high risk of death in the immediate post-HCT period in part due to disease recurrence (relapse-related mortality [RM]), but also due to treatment-related mortality (TRM) resulting from the following: i) toxicity due to high intensity treatment; ii) graft vs. host disease (GvHD) and its management; and iii) infections. Previous studies utilizing data from HCTs performed in 1980s and 1990s indicate that the 1-yr cumulative incidence of TRM exceeds 20% for related donor and 30% for unrelated donor HCTs. However, gaps in knowledge remain related to the cause-specific cumulative incidence of TRM and RM after autologous and allogeneic HCT performed in the more recent eras. Methods:Between 2005 and 2008, a total of 1,673 consecutive patients received HCT at City of Hope at a median age of 50 years for AML (n=433), NHL (n=428), MM (n=369), ALL (n=176), and HL (n=154); 913 patients received autologous HCT; 382 allogeneic related donor; and 378 unrelated donor HCT. Reduced intensity conditioning was used for 268 patients. Early mortality was defined as death in the first year after HCT due to disease (RM) or treatment (TRM). Information regarding vital status and cause of death were obtained from medical records, supplemented with Social Security Death Index. Overall survival (OS) and cumulative incidence of TRM and RM were calculated for 30 d, 6 mo and 1 yr after HCT for i) the entire cohort, and by ii) diagnosis and iii) type of HCT. Multivariable models identified predictors of TRM and RM. Results:A total of 323 deaths (19.3% of the entire cohort) were observed within the first year after HCT; 55.5% attributed to TRM and 44.5% to RM. Among deaths due to TRM, 59% were attributed to infections, 12.9% to acute or chronic GvHD, and 9.5% to organ toxicity. Among autologous, related and unrelated donor HCT recipients, overall survival (OS) was 87.2%, 76.6% and 63.5% at 1 yr (p<0.001) (Figure 1A). Among autologous, related donor, and unrelated donor HCT recipients, 1-yr cumulative incidence of TRM was 1.6%, 12.1%, and 25.6% respectively (p<0.001) (Figure 1B), and cumulative incidence of RM was 8.2%, 6.9%, and 8.7% respectively (p=0.73) (Figure 1C). OS and cumulative incidence of TRM and RM by disease and type of HCT are summarized in Table. Predictors of increased RM included age at HCT 40–60 yr (HR: 1.6, p=0.04; referent group: <40 yr), and diagnosis of NHL (HR=2.0, p=0.008; referent group: AML); receipt of HCT in the later years was associated with decreased RM (2007: HR=0.5, p=0.02; 2008: HR=0.5, p=0.04; referent group: HCT in 2005). Of note, RM for NHL and AML did not differ by type of HCT (p=0.94). Predictors of TRM included allogeneic HCT (related: HR=4.3, p=0.0003; unrelated: HR=10.2, p<0.0001; referent group: autologous HCT). Among related and unrelated HCT recipients, use of reduced intensity conditioning did not have a significant impact on TRM (HR=1.2, p=0.6) or RM (HR=1.2, p=0.7). Conclusion:For patients with NHL and AML, cumulative incidence of RM does not differ by HCT type. Unrelated donor HCT continues to be associated with the highest risk of TRM. Infection is the most frequent cause of TRM, accounting for 62% of deaths due to TRM in unrelated donor, 52% in related donor, and 46% in autologous HCT recipients – reinforcing the need for aggressive measures for prevention and treatment of infections in this immune compromised population.Overall survivalCum incidence: TRMCum incidence RRM30 d6 mo1 yr30 d6 mo1 yr30 d6 mo1 yrEntire cohort (n=1673)98.7%88.8%79.1%1.2%6.7%9.7%0.1%3.7%8%Autologous HCT (n=913)99.6%94.8%87.2%0.5%1.1%1.6%02.9%8.2%Allogeneic HCT (n=382)98.7%87%76.6%0.8%8.2%12.1%0.6%4.3%6.9%URD HCT (n=378)96.6%77%63.5%3.6%17.9%25.6%0%5%8.7%Autologous (AML: n=67)98.5%95.2%85.3%1.5%4.8%6.4%0%0%8.2%Related donor (AML: n=175)98.9%85.3%72.4%0.6%10.1%14%0.6%4.4%8.3%URD HCT (AML: 191)97.4%75%62.9%2.7%19.3%25.1%05%9.1%Related donor (ALL: n=89)97.8%89.7%80.3%2.4%8.5%13.6%0%0%0%URD HCT (ALL: n=87)93.3%72.8%57.8%6.7%21.5%33.1%05.7%9.2%Autologous (NHL: n=313)100%91.2%82%0%0%0.4%0%6.6%13.7%Related donor (NHL: n=63)98.4%81.6%68.9%0%8.5%14.2%0%10.5%14.3%URD HCT (NHL: n=52)98.1%82.4%70.7%1.9%9.9%16.5%0%7.9%11.9%Autologous (HL: n=147)99.3%94.2%87.2%0.7%2.2%2.2%0%2.2%7%Autologous (MM: n=358)99.7%98.4%92.6%0.3%0.6%1.3%0%0.7%3.9% [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prognostic Significance of Interim 18f-FDG PET/CT for the Treatment of Diffuse Large B-Cell Lymphoma In the Post-Rituximab Era.

AbstractAbstract 179918F-fluoro-2-dexoy-D-glucose-positron emission tomography (FDG-PET)/computerized tomography (CT) has been used for staging and monitoring responses to treatment in patients with diffuse large B cell lymphoma (DLBCL). The sequential interim PET/CT was prospectively investigated to determine whether it provided additional prognostic information and could be a positive predictable value within patients with the same international prognostic index (IPI) after the use of rituximab in DLBCL. Patients and methods:One hundred and sixty-one patients with newly diagnosed DLBCL were enrolled between August 2004 and December 2009 at a single institution. The assessment of the PET/CT was performed at the time of diagnosis and mid-treatment of R-CHOP chemotherapy. The clinical stage and response of the patients were assessed according to revised response criteria for aggressive lymphomas (Cheson, J Clin Oncol, 2007). The positivity of interim PET/CT was determined based on the semi-quantitative assessment of the maximal standardized uptake value (SUVmax cut-off value of 3.0). Results:Sixty-seven patients (41.6%) presented in advanced stage disease and 27 (16.8%) had bulky lesions. At diagnosis, 53 patients (32.9%) were classified as high/high-intermediate risk by the IPI and two patients could not check the interim response due to treatment-related mortality (TRM). Forty-three patients (26.7%) continued to have positive metabolic uptakes with a significantly high relapse rate (62.8%) compared to the patients with a negative interim PET/CT (12.1%) (P<0.01). After a median follow-up of 30.8 months, the positivity of interim PET/CT was found to be a prognostic factor for both OS and PFS, with a hazard ratio of 4.07 (2.62 – 6.32) and 5.46 (3.49 – 8.52), respectively. In the low-risk IPI group, the 3-year OS and PFS rate was significantly different in the patients with positive (53.3 and 52.5%) and negative (93.8 and 88.3%) interim PET/CT, respectively (P<0.01). These significant prognostic differences of interim PET/CT responses were consistent with the results of the patients with high-risk IPI group (P< 0.01). Conclusions:Interim PET/CT scanning had a significant predictive value for disease progression and survival of DLBCL in post-rituximab treatment; it might be the single most important determinant of clinical outcome in patients with the same IPI risk. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Assessment of the Hematopoietic Cell Transplantation Comorbidity Index in Non-Hodgkin Lymphoma Patients Receiving Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation

The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatment-related mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on OS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell–replete allografts from HLA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy ( P = .0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor ( P < .0001) relative to OS, and there was a trend ( P = .056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT.

Improvement of Induction Remission Rate by Modifying the Dose of Idarubicin for Relapsed Childhood Acute Lymphoblastic Leukemia

Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL), yet there is no established treatment for relapsed ALL. To improve the induction remission rate, we modified the dose of idarubicin in the original Children's Cancer Group (CCG)-1884 protocol, and retrospectively compared the results. Twenty-eight patients diagnosed with relapsed ALL received induction chemotherapy according to the CCG-1884 protocol. Complete remission (CR) rate in all patients after induction chemotherapy was 57%. The idarubicin 10 mg/m2/week group showed CR rate of 74%, compared with the 22% CR rate of the idarubicin 12.5 mg/m2/week group (p=0.010). Remission failure due to treatment-related mortality (TRM) was 44% and 5.2% in the idarubicin 12.5 mg/m2/week and 10 mg/m2/week groups, respectively (p=0.011). Overall survival (OS) and 4-yr event-free survival (EFS) were 12.8% and 10.3%, respectively. OS and 4-yr EFS were higher in the idarubicin 10 mg/m2/week group (19.3% and 15.6%) than in the 12.5 mg/m2/week group (0% and 0%). In conclusion, a modified dose of idarubicin from 12.5 mg/m2/week to 10 mg/m2/week resulted in an improved CR rate in the treatment of relapsed ALL, which was due to lower TRM. However, despite improved CR rate with modified dose of idarubicin, survival rates were unsatisfactory.

Second Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction: In acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), relapse after allogeneic stem cell transplantation (SCT) occurs with frequencies of 30–80% in dependence on risk profiles. Selected patients are offered a 2. allo-SCT. As the number of studies is limited, we here performed retrospective analysis of 20 consecutive MDS and AML pts who received at least 2 allografts from related/unrelated donors from 2000–2007. Patients: There were 4 children and 16 adults who received ≥2 allo-SCTs (10 males, 10 females; 2–63 years, median 38 yy). 14 pts had de novo AML, 3 pts s-AML, 2 MDS RAEB-1; one child had juvenile myelomonocytic leukemia (JMML). 19 pts received two allo-SCTs-18 due to another relapse after the 1. allo-SCT, one due to secondary graft failure after 1. SCT. One pt with MDS had 3 allo-SCTs due to relapses. 13/20 pts received treatment before the 2. allo-SCT, but only 6/20 achieved complete remission (CR). 10/20 pts had unfavorable cytogenetics. The median interval between the 1. and 2. allo-SCTs was 20 months (range 2–47 mo). Median disease free survival (DFS) after the 1. SCT was 16 months (range 3–45 mo). Characterization of 2. allo-SCTs: 4/20 second allo-SCTs were performed from related donors (3 HLA-identical, one haploidentical). 16 SCTs were performed from unrelated donors (HLA matched: n= 8, -mismatched: n=8). In 10 cases, the 2. allo-SCTs was performed from different, in 10 cases from the same donor. Reduced intensity conditioning was applied to 16 pts, myeloablative to 4 pts. Antithymocyte globuline was administered to 12/20 pts. One pt received bone marrow, 19 pts peripheral blood stem cells. Immunosuppression was performed in most pts by cyclosporine A plus short-course MTX or mycophenolate mofetil. Outcomes: Leukocyte engraftment was achieved in 16/20 cases with a median interval of 13 days (r. 10–24 d). 3 pts died prior to engraftment. One pt had secondary graft failure being followed by a 2. allo-SCT. CR was achieved by 16/20 pts. At the time of this report, 5/20 pts are still alive after a median follow-up of 15 months (r. 2–36 mo), three of those in CR with follow-ups of 7, 22, and 36 months. 9/20 pts developed relapse (45%), of whom 2 received donor lymphocytes. Median DFS after the 2. SCT was 7 months (range <1–38 mo). One patient received a 3. allo-SCT after another relapse of AML, but died 8 months after 3rd SCT due to treatment related mortality (TRM). The TRM rate was 7/20 pts (35%) either due to sepsis and multiorgan failure, fungal pneumonia, or acute GvHD. AGvHD (II–IV) was described in 11/20 pts (55%). Chronic GvHD developed in 5/20 pts. Two of those 3 pts, who remained in stable CR, had unfavorable karyotypes. They had developed relapse after 3, 28, and 45 months following the 1. SCT. Two achieved CR before the 2. allo-SCT. In two cases, HLA-mismatched SCTs were performed being followed by extensive cGVHD. All had reduced conditioning before SCT. One of those, a male pt aged 16 years, primarily received no immunosuppression. Following severe intestinal aGvHD after 3 weeks tacrolimus and steroids were started. Discussion: Despite a high rate of reduced intensity conditioning, TRM (35%) and relapse rate were high (45%). However, single pts seemed to benefit from a 2. SCT, even in case of unfavourable karyotypes or when no complete remission was achieved before the 2. SCT, and here also in one case with an early relapse after the 1. SCT. Thus, it seems difficult to predict which patients might have a benefit from this approach. Research should focus on the optimization of conditioning regimens especially for recipients of a 2. SCT and try to provide concepts for immunosuppression in this specific situation due to the high relapse risk.

Bone Marrow Hypocellularity, Decreased Platelet Counts and Colony Forming Units Serve as Prognostics Parameters for Early Events after Auto-Peripheral Blood Stem Cell Transplantation.

High-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-PBSCT) offers a valid treatment option in cancer patients (pts) with advanced, relapsed or high-risk (HR) disease. Auto-PBSCT is in general a safe procedure, however, some pts at risk may have a dismal outcome due to treatment related mortality (TMR), early relapse/progression (ER) and/or failure of blood cell reconstitution (FBR). Risk factors predisposing for early events after PBSCT have not yet been clearly assessed. From a total of 796 pts having been transplanted over a 10 year (y) period (6/93–5/03), we determined 50 pts (group A, m:f=29:21), who had primary FBR or died within 3 months after PBSCT. As a control group, 50 pts who had undergone PBSCT over the same period, were randomly selected (group B; m:f=25:25). Pre-PBSCT-parameters associated with early complications were examined by univariate analysis. Median age at transplant was similar in group A (52y) and B (54y). Group A vs. B had underlying lymphoma in 31 vs. 17, solid tumors in 13 vs. 21 and leukemias in 6 vs. 12 pts, respectively. Notable differences were a lower performance status, more pretreatment chemotherapy (CX)-cycles, higher LDH levels, lower platelet counts, hypocellular bone marrow (BM) and lower colony forming units (CFU) in group A. Treatment before PBSCT in group A consisted of a median number of 7 CX (group B: 4 CX) cycles. Median number of retransfused CD34+-cells were similar (group A 4.1 vs. group B 3.7×10e6/kg bw). Total CFUs/1.5e5, determined by methylcellulose culture of PBSC grafts in group A were decreased with 128 vs. 187 (group B), and BFU-E, CFU-GM, and CFU-GEMM were 51 vs. 79, 55 vs. 87 and 5 vs. 4, respectively. Hypocellular BM was observed in group A and B in 46% vs. 4% of pts (odds ratio 20.44 [p<0.001]), platelet counts were 98 vs. 170×10e9/L (odds ratio 13.5 [p<0.001]), respectively. Advanced stage at transplant was present in 90% vs. 78%, and residual BM-infiltration in 36% vs. 58% in group A and B. Age, number of CX-cycles and CD34+-transfused cells showed no significantly increased risk. Of pts in group A, 21 had early TRM (group A1: sepsis and multi-organ failure in 81%, fatal bleeding in 14%, CX-toxicity in 5%; death after median of 23 days [d]). 26 pts (52%) died of early progression (group A2: after a median of 62d) and 3 pts (6%) had FBR (group A3). Median BFU-E, CFU-GM and CFU-GEMM were similar in group A1 and A2 and correlated with comparable CD34+-numbers. However, in group A1, 29% reached no WBC and 81% no platelet engraftment, whereas in group A2 only 12% and 23% did not reach WBC- and platelet reconstitution, respectively. Engraftment in group B (control pts) was regular (median WBC and platelet reconstitution on d+10). With a TRM of 2.64% and FBR in 0.38% in this HR-pt cohort, auto-PBSCT is in general a well tolerable treatment option. Nevertheless, distinct risk factors for early complications can be determined and should be considered. We identified BM-hypocellularity and a decreased platelet count <100×10e9/L as the strongest prognostic parameters. Our analysis also suggests, that other pre-transplant parameters, including CFUs - more reliably than CD34+-cell numbers - provide additional valuable information on engraftment and relevant events after auto-PBSCT.

Bone Marrow Hypocellularity, Decreased Platelet Counts and Colony Forming Units Serve as Prognostics Parameters for Early Complications after Autologous Peripheral Blood Stem Cell Transplantation.

High-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-PBSCT) offers a valid treatment option in cancer patients (pts) with advanced, relapsed or high-risk (HR) disease. Auto-PBSCT is in general a safe procedure, however, some pts may have a dismal outcome due to treatment related mortality (TMR), early relapse (ER) and/or failure of blood cell reconstitution (FBR). Risk factors predisposing for early complications after PBSCT have not yet been clearly assessed. From a total of 796 pts having been transplanted over a 10 year (y) period (6/93-5/03), we determined 50 pts (group A, m:f=29:21), who had primary FBR or died within 3 months after PBSCT. As a control group, 50 pts who had undergone PBSCT over the same period, were randomly selected (group B; m:f=25:25). Pre-PBSCT-parameters associated with early complications were examined by univariate analysis. Median age at transplant was similar in group A (52y) and group B (54y). Group A vs. B had underlying lymphoma in 31 vs. 17, solid tumors in 13 vs. 21 and leukemias in 6 vs. 12 pts, respectively. Notable differences were a lower performance status, more pretreatment chemotherapy (CX)-cycles, higher LDH levels, lower platelet counts, hypocellular bone marrow (BM) and lower colony forming units (CFU) in group A. Treatment before PBSCT in group A consisted of a median number of 7 CX (group B: 4 CX) cycles. Median number of retransfused CD34+-cells were similar (group A 4.1 vs. group B 3.7x10e6/kg bw). Total CFUs/1.5e5, determined by methylcellulose culture of PBSC grafts in group A were considerably decreased with 128 vs. 187 (group B), and BFU-E, CFU-GM, and CFU-GEMM were 51 vs. 79, 55 vs. 87 and 5 vs. 4, respectively. Hypocellular BM was observed in group A and B in 46% vs. 4% of pts (odds ratio 20.44 [p<0.001]), platelet counts were 98 vs. 170x10e9/L (odds ratio 13.5 [p<0.001]), respectively. Advanced stage at transplant was present in 90% vs. 78%, and residual BM-infiltration in 36% vs. 58% in group A and B, respectively. Age, number of CX-cycles and CD34+-transfused cells showed no significantly increased risk. Of pts in group A, 21 had early TRM (group A1: sepsis and multi-organ failure in 81%, fatal bleeding in 14%, CX-toxicity in 5%, leading to early death after a median of 23 days [d]). 26 pts (52%) died of early progression (group A2: after a median of 62d) and 3 pts (6%) had FBR (group A3). Median BFU-E, CFU-GM and CFU-GEMM were similar in group A1 and A2 and correlated with comparable CD34+-numbers. However, in group A1, 29% reached no WBC and 81% no platelet engraftment, whereas in group A2 only 12% and 23% did not reach WBC- and platelet reconstitution, respectively. Engraftment in group B (control pts) was regular with median WBC and platelet reconstitution on d+10. With a TRM of 2.64% and FBR in 0.38% in this HR-pt cohort, auto-PBSCT is in general a well tolerable treatment option. Nevertheless, distinct risk factors for early transplant complications can be determined and should be considered. We identified BM-hypocellularity and a decreased platelet count <100x10e9/L as the strongest prognostic parameters. Our analysis also suggests, that other pre-transplant parameters, including CFUs - more reliably than CD34+-cell numbers - provide additional valuable information on engraftment and complications after auto-PBSCT.