Patients Receiving Stem Cell Transplantation Research Articles

Development of a Web-Based Intervention for Addressing Distress in Caregivers of Patients Receiving Stem Cell Transplants: Formative Evaluation With Qualitative Interviews and Focus Groups

BackgroundCaregivers of cancer patients experience significant burden and distress including depression and anxiety. We previously demonstrated the efficacy of an eight session, in-person, one-on-one stress management intervention to reduce distress in caregivers of patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCT).ObjectiveThe objective of this study was to adapt and enhance the in-person caregiver stress management intervention to a mobilized website (eg, tablet, smartphone, or computer-based) for self-delivery in order to enhance dissemination to caregiver populations most in need.MethodsWe used an established approach for development of a mhealth intervention, completing the first two research and evaluation steps: Step One: Formative Research (eg, expert and stakeholder review from patients, caregivers, and palliative care experts) and Step Two: Pretesting (eg, Focus Groups and Individual Interviews with caregivers of patients with autologous HSCT (auto-HSCT). Step one included feedback elicited for a mock-up version of Pep-Pal session one from caregiver, patients and clinician stakeholders from a multidisciplinary palliative care team (N=9 caregivers and patient stakeholders and N=20 palliative care experts). Step two included two focus groups (N=6 caregivers) and individual interviews (N=9 caregivers) regarding Pep-Pal’s look and feel, content, acceptability, and potential usability/feasibility. Focus groups and individual interviews were audio-recorded. In addition, individual interviews were transcribed, and applied thematic analysis was conducted in order to gain an in-depth understanding to inform the development and refinement of the mobilized caregiver stress management intervention, Pep-Pal (PsychoEducation and skills for Patient caregivers).ResultsOverall, results were favorable. Pep-Pal was deemed acceptable for caregivers of patients receiving an auto-HSCT. The refined Pep-Pal program consisted of 9 sessions (Introduction to Stress, Stress and the Mind Body Connection, How Thoughts Can Lead to Stress, Coping with Stress, Strategies for Maintaining Energy and Stamina, Coping with Uncertainty, Managing Changing Relationships and Communicating Needs, Getting the Support You Need, and Improving Intimacy) delivered via video instruction through a mobilized website.ConclusionsFeedback from stakeholder groups, focus groups, and individual interviews provided valuable feedback in key areas that was integrated into the development of Pep-Pal with the goal of enhancing dissemination, engagement, acceptability, and usability.

Clinical and Biological Features of Pediatric Acute Myeloid Leukemia with Primary Induction Failure in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Study

INTRODUCTIONTreatment outcome of pediatric acute myeloid leukemia (AML) patients has improved over the past few decades due to intensive chemotherapy. Primary induction failure (PIF), defined as failure to achieve complete remission after the second induction chemotherapy, occurs in around 10% of children with newly diagnosed AML. Effective treatment strategy for these patients is not established and their poor prognoses have been reported elsewhere. Here we investigated the clinical and biological features of pediatric AML patients with PIF who were registered in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Study (AML-05). METHODSWe conducted a retrospective survey of patients who were registered in the AML-05. We analyzed probabilities of overall survival (OS) according to gender, age at diagnosis, white blood cell count (WBC) at diagnosis, FAB classification, etc. Genetic analysis of primary leukemic blasts was performed. We screened fusion genes and gene mutations as follows: RUNX1-RUNX1T1, CBFB-MYH11, NUP98-NSD1, DEK-NUP214, MLL-PTD, WT1, NPM1, and MLL-rearrangements, gene mutations of KIT and FLT3-ITD. Furthermore, we evaluated the clinical and biological background of these PIF patients to define their prognostic factors statistically. RESULTS: Among the 443 patients registered in the AML-05 between November 2006 and December 2010, 43 patients (9.7%) had PIF. The observation period from the date of PIF was 5-78 months (median, 20 months). The age at diagnosis was 0.1-17 years (median, 6.1 years). There was no significant difference in gender (28 males vs15 females). The 3-year OS rate was 19.0% (95% confidence interval 1.0%-38.0%). This was extremely poor compared to the patients who achieved complete remission (CR): 66.7% for high-, 73.2% for intermediate-, and 92.6% for low-risk groups, respectively. Disease recurrence is the major cause of death (n=19, 46.3%). The mean WBC at diagnosis of PIF patients was 96 x 109/L: this is significantly higher than that of non-PIF patients (51 x 109/L, P<0.01, Cox regression analysis). Morphologically, FAB classification M7 was more frequently detected in the PIF group compared with non- PIF group, although not statistically significant: 11 patients (25.6%) vs 43 patients (9.1%) (P=0.07). Unfavorable prognostic cytogenetics such as FLT3-ITD (n=16, 37.2%), NUP98-NSD1 (n=6, 15.4%), and complex karyotype (n=9, 20.9%) were detected more frequently in PIF patients, as well as MLL-PTD (n=7, 16.2%), c-KIT mutations (n=6, 14.0%), DEK-NUP214 (n=2, 4.7%), and monosomy 7 (n=6, 14%). There were no cases with WT1 or NPM1 mutations. Only 3 patients had core binding factor leukemia with RUNX1-RUNX1T1 or CBFB-MYH11 in the PIF patients. Thirty-seven PIF patients received stem cell transplantation (SCT). The patients without SCT did not achieve CR, and died of primary disease. The patients who had achieved CR before SCT showed significantly better OS (P=0.03). There was no significant difference in donor source and conditioning regimen. Younger age at diagnosis (<10 years of age, P=0.02) was associated with better outcome. High-dose cytarabine-containing re-induction chemotherapy seemed effective on univariate analysis, which indicates the type of re-induction chemotherapy to be prognostic. Finally, multivariate analysis showed only age at diagnosis (<10 years of age) to be a significant prognostic factor. CONCLUSIONSThe prognosis of pediatric AML patients with PIF was extremely poor. In our survey, unfavorable molecular biological background of leukemia was associated with PIF. It is necessary to explore more effective treatment strategies based on leukemia biology for these patients in the future. DisclosuresNo relevant conflicts of interest to declare.

Patient Characteristics, Treatment Patterns and Outcomes Among Relapsed/Refractory Multiple Myeloma (RRMM) Patients in Japan

BackgroundMM is one of the most common hematologic malignancies in Japan and deaths due to MM represent 1.1% of all cancer deaths in 2014. Proteasome inhibitors and immunomodulatory drugs have led to improvements in overall survival (Kumar et al. Blood 2008); a trend that was confirmed in a large retrospective analysis of Japanese patients across the years 2001-2012 (Ozaki, et al, Blood Cancer Journal, 2015). The Japan Society of Hematology guideline for MM and guidelines for diagnosis and management of MM by the Japanese Myeloma Study Group recommend bortezomib (approved 2006), thalidomide (approved 2008) and lenalidomide (approved 2010) along with other anti-MM agents for treatment of RRMM. The objective of this study is to describe patient characteristics, contemporary treatment patterns, and outcomes in patients with RRMM using real world data.MethodPatients with MM diagnoses based on ICD-10-CM (C900) codes, during the study period of April 2008 to January 2016, were followed using Japanese health insurance claims data provided by Medical Data Vision (MDV) in this retrospective cohort study. Index date was defined as the first observed claim for MM treatment after at least 90 days of washout period from enrollment. Progression to a subsequent line of therapy was defined as switch to another drug combination > 60 days from index date or retreatment following a treatment gap of > 90 days. Time to next treatment (TTNT) was used as a disease progression proxy and was measured as the time from the start date of the line of therapy to the start date of a subsequent line of therapy. Descriptive analyses were carried out to examine patient characteristics, treatment patterns and outcomes. Observations were censored at time of loss to follow up/end of study period.ResultsAmong a total of 12,348 patients with a diagnostic code of MM between April 2008 and January 2016, 358 patients who received at least one treatment episode were identified with RRMM. Median follow-up was 34.0 months. Median age was 71.0 years; 34% were aged 65-74 years and 35% were 75 years or older. Male patients constituted 56%, however female patients over 80 years outnumbered male patients. Cytogenetic testing was performed in 70%. Thirteen percent of patients received stem cell transplant and 22% of those were over 65 years. Across the lines of therapy for RRMM, the regimens were: bortezomib (V) ± dexamethasone (d) (V ± d, 27.7%), melphalan (M) + prednisone (P) (MP, 20.9%), lenalidomide (R) ± d (10.9%), VM ± P (4.2%), V-cyclophosphamide (C) ± d (VC ± d, 3.1%), V + other (2%), R + other (0.3%), and others (50.0%). Among patients treated with others, a corticosteroid alone such as dexamethasone or prednisone was commonly used and alkylating agents or thalidomide were also used. Among patients treated with V-based regimen, 75% had at least one medical claim for acyclovir or valacyclovir for prophylaxis against risk of infection. Among patients treated with R-based regimen, 69% had at least one medical claim for aspirin, enoxaparin or warfarin for thromboembolism prophylaxis. Median duration of treatment was 5.1 months for patients with V ± d, 5.2 months for patients with MP and 5. 3 months for patients with R ± d. Median daily dose of R was 13.3 mg. Median TTNT for patients treated with V ± d, MP and R ± d was 11.5 months, 8.4 months and 12.5 months, respectively.ConclusionThis is the first database analysis based on health insurance claims data of MM in Japan. This analysis of treatment patterns found that doublet regimens were used mainly in Japanese patients with RRMM, with V ± d and MP regimens being the most common. The duration of each regimen was relatively short and the majority of patients discontinued therapy prior to disease progression. Recent evidence has shown triplet regimens have better efficacy than doublet regimens among RRMM patients. Triplet regimens containing novel agents with sustainable efficacy, and a manageable safety and tolerability may increase the likelihood of prolonged therapy which has been correlated with better outcomes over fixed duration therapy in MM. This study may underestimate the duration of each treatment since the data were not censored. DisclosuresJun:Takeda Pharmaceutical Company Limited: Employment. Luptakova:Takeda Oncology: Employment. Koizumi:Takeda Pharmaceutical Company Limited: Consultancy. Iwasaki:Takeda Pharmaceutical Company Limited: Consultancy. Hiroi:Takeda Pharmaceutical Company Limited: Employment. Soeda:Takeda Pharmaceutical Company: Employment.

Azithromycin modulates immune response of human monocyte-derived dendritic cells and CD4+ T cells

Azithromycin (AZM) is a macrolide antibiotic that exhibits anti-inflammatory activity aside from its antimicrobial effect, a feature that may ameliorate certain inflammatory disorders and prevent graft-versus-host disease in patients receiving stem cell transplantation. In the present study, we investigated the ability of AZM to influence the function of human monocyte-derived dendritic cells (DCs) and CD4+ T cells. We found that AZM down-regulated CD80, CD86, and HLA-DR expression in lipopolysaccharide (LPS)-stimulated DCs and suppressed interleukin (IL)-6, IL-10, IL-12, and tumor necrosis factor-alpha production in these cells. In addition, AZM increased endocytosis and/or expression of Toll-like receptor (TLR)2, TLR4, and TLR9 in DCs and suppressed anti-CD3/CD28–induced CD4+ T cell proliferation and interferon-gamma production, an effect that was synergistic with dexamethasone. Finally, AZM suppressed DC-induced allogeneic T cell proliferation and cytokine production. Our study demonstrates that AZM modulates DC and CD4+ T cell function and may be of therapeutic benefit in various inflammatory disorders.

Low-Level Laser Therapy Used in Prevention of Oral Mucositis for Patients Receiving Stem Cell Transplant

Low-Level Laser Therapy Used in Prevention of Oral Mucositis for Patients Receiving Stem Cell Transplant

Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Diagnostic Patterns Among United States and European Union Hematologists and Oncologists Managing Patients Receiving Stem Cell Transplantation

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially fatal complication of hematopoietic stem cell transplantation (HSCT) and high-dose chemotherapy. The VOD/SOS pathologic cascade is initiated by endothelial and hepatocyte damage. VOD/SOS is usually diagnosed using Baltimore criteria (≤21 days post transplant: bilirubin >2 mg/dL, plus 2 or more of hepatomegaly, ascites, and weight gain ≥5%) or modified Seattle criteria (≤20 days post transplant: 2 or more of bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain >2%). Severe VOD/SOS, usually characterized by multi-organ dysfunction (ie, pulmonary and/or renal dysfunction), may develop in a substantial number of high-risk patients and may be associated with >80% mortality. To understand the diagnostic patterns for VOD/SOS in the United States (US) and European Union (EU), a quantitative online survey was conducted among HSCT specialists. Methods Participating hematology-oncology specialists for pediatric and adult patients had ≥2 years direct involvement in performing HSCT, spent ≥25% of their time in direct patient care, and managed ≥10 HSCT patients (≥10 allogeneic) in the past year. Their facilities were accredited and performed ≥80 adult HSCT procedures in the US (≥50 in the EU) or ≥20 pediatric HSCT procedures (US or EU). In this survey, VOD/SOS severity was rated as early (milder) or severe (with multi-organ dysfunction). On average, the online survey took 30 to 40 minutes to complete. Results Surveys were completed by 100 US physicians (70 adult, 30 pediatric) and 153 EU physicians (122 adult, 31 pediatric; from France, Germany, Italy, Spain, and the United Kingdom). Each physician directly managed an average of 179 (US) or 95 (EU) HSCT patients in the past year. In adult patients, the median percentages of patients treated for severe/early VOD/SOS were 7%/7% in the US and 3%/6% in the EU; in pediatric patients, the median percentages were 9%/12% in the US and 5%/10% in the EU. The most commonly used VOD/SOS diagnostic signs and symptoms (Table) were weight gain and bilirubin level. The median level of weight gain to trigger follow-up action (action not specified but could include further diagnostic testing) was 10% in the US and 5% in the EU, for both adult and pediatric patients; the Baltimore and Seattle criteria specify a weight gain of 5% and 2%, respectively. US physicians were less likely than EU physicians to take action at weight gain of ≤5% (Figure): about half as likely for adults (29% vs 56%) and about a fifth as likely for pediatric patients (14% vs 67%). In addition, at ≤5% weight gain, US physicians of pediatric patients were about twice as likely to take action as US physicians of adult patients. The median bilirubin levels at which US physicians initiated action were 3 mg/dL in adults and 4 mg/dL in pediatric patients, compared with 2 mg/dL for EU physicians in both adult and pediatric patients (Figure); the Baltimore and modified Seattle criteria specify a bilirubin level of 2 mg/dL. Conclusions The survey results show that a substantial proportion of US HSCT physicians take follow-up action at weight gain or bilirubin thresholds higher than those in the Baltimore or modified Seattle criteria. Treatment patterns in the EU, particularly among pediatric physicians, appear to be more closely aligned with the diagnostic criteria. The established criteria have limitations; neither set takes into account late onset of VOD/SOS or presentation of edema and weight gain in the absence of other signs and symptoms. As discussed in a recent publication (Mohty M et al. BMT. 2015;50[6]:781-789), elevated bilirubin may be absent in VOD/SOS developing late after HSCT and in children, which prompted the authors to suggest the need for a criteria update. Support: Jazz Pharmaceuticals. Participants received financial remuneration for their survey participation. Disclosures Corn:Jazz Pharmaceuticals: Employment, Equity Ownership. Ogram:Jazz Pharmaceuticals: Employment, Equity Ownership. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership.

Prognostic Relevance of Recurrent Genetic Aberrations in Pediatric Acute Megakaryoblastic Leukemia

Genetic abnormalities and early treatment response are the main prognostic factors in pediatric acute myeloid leukemia (AML). Non-Down Syndrome (non-DS) acute megakaryoblastic leukemia (AMKL) is a rare subtype of AML, with a poor prognosis. These cases present with diverse cytogenetic aberrations, which might be important for risk-group stratification. A well-known genetic aberration in non-DS-AMKL is t(1;22)(p13;q13), resulting in expression of the RBM15/MKL1(OTT/MAL) fusion transcript. In recent years, targeted and genome-wide sequencing has identified novel, recurrent molecular abnormalities in pediatric AMKL. New fusions identified are inv(16)(p13.3q24.3) resulting in CBFA2T3/GLIS2 (Gruber et al, Cell, 2012; Masetti et al, Blood, 2013) and t(11;12)(p15;p13) resulting in NUP98/KDM5A (de Rooij et al, Leukemia, 2013) as specific aberrations in pediatric non-DS AMKL. Also KMT2A(=MLL)-rearrangements are recurrent in non-DS AMKL. The prognostic relevance of these novel abnormalities is not determined in a large cohort, since this disease is rare.To assess frequencies, clinical characteristics and outcome parameters of recurrent cytogenetic aberrations of pediatric non-DS AMKL, databases of the BFM-SG, DCOG, AIEOP, and COG were combined. In this study, we analyzed 151 newly diagnosed pediatric non-DS AMKL cases diagnosed between 1998 and 2014 of whom a sample was available. All patients included were screened for NUP98/KDM5A, CBFA2T3/GLIS2 and RBM15/MKL1 with reverse transcriptase(RT-) PCR,and for KMT2A-rearrangements using split signal FISH and RT-PCR. To assess outcome, probability of event-free survival (pEFS) and probability of overall survival (pOS) were estimated by the Kaplan-Meier method, and groups were compared with the log-rank test; the cumulative incidence of non-response or relapse (pCIR) was analysed by the Kalbfleisch and Prentice method, and groups were compared with the Gray's test. A Cox regression analysis was done for EFS and relapse incidence with as co-variables cytogenetic subgroup, age, sex, WBC and stem cell transplantation (time dependent variable).Patients were treated with different protocols; however, all protocols consisted of intensive chemotherapy using an anthracycline and cytarabine backbone for both induction and consolidation; 26% of patients received stem cell transplantation (SCT) in first remission. Median age was 1.6 years (range 0.1-17.1 years), with 62% of the patients younger than 2 years at diagnosis; 45% of patients were males, and median white blood cell count was 13.7x109/L (range 1.1-378.5x109/L). Translocation NUP98/KDM5A was identified in 9%; the CBFA2T3/GLIS2 translocation in 16%; RBM15/MKL1 in 12% and KMT2A-rearrangements in 9%, and hence in 54% none of these abnormalities were detected. All these aberrations were mutually exclusive. Comparing patients with NUP98/KDM5A, CBFA2T3/GLIS, RBM15/MKL1, or KMT2A-rearrangements with other pediatric AMKL patients, no significant differences in sex, age, and white blood cell count were found. Outcome between the included collaborative groups did not differ significantly. The 5-year pOS of the entire pediatric non-DS AMKL cohort was 56±4%, 5-year pEFS was 51±4%. NUP98/KDM5A, CBFA2T3/GLIS2 and KMT2A-rearranged positive patients showed a poor outcome (pOS 36±13%, 38±10%, and 38±13% respectively), compared to RBM15/MKL1 positive cases and other pediatric non-DS AMKL (70±11% and 65±5% respectively, p=0.04, Figure 1). Harboring NUP98/KDM5A, CBFA2T3/GLIS2 or a KMT2A-rearrangement resulted in an increased risk of experiencing an event (EFS; HR1.65, 95%CI;1.03-2.66, p=0.039) or relapse (RFS; HR2.14, 95%CI;1.12-4.11, p=0.022). SCT was not an independent factor for event or relapse free survival (HR1.20, 95%CI;0.65-2.20, p=0.565 and HR 1.13, 95%CI;0.57-2.24, p=0.717, respectively), nor did sex, age at diagnosis or WBC.Our results indicate that non-DS AMKL is a heterogeneous group within pediatric AML. Although the overall survival is poor for non-DS AMKL in general with a 5-yr pOS of ~55%, the poor outcome is specifically determined by cases with NUP98/KDM5A, CBFA2T3/GLIS2 and KMT2A-rearrangements. Other variants, including those with RBM15/MKL1, are associated with a better outcome. These data show that international collaboration allows the identification of prognostic subgroups, which may lead to new and more refined risk-group stratification. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Diagnostic Patterns Among United States and European Union Hematologists and Oncologists Managing Patients Receiving Stem Cell Transplantation

IntroductionHepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially fatal complication of hematopoietic stem cell transplantation (HSCT) and high-dose chemotherapy. The VOD/SOS pathologic cascade is initiated by endothelial and hepatocyte damage. VOD/SOS is usually diagnosed using Baltimore criteria (≤21 days post transplant: bilirubin >2 mg/dL, plus 2 or more of hepatomegaly, ascites, and weight gain ≥5%) or modified Seattle criteria (≤20 days post transplant: 2 or more of bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain >2%). Severe VOD/SOS, usually characterized by multi-organ dysfunction (ie, pulmonary and/or renal dysfunction), may develop in a substantial number of high-risk patients and may be associated with >80% mortality.To understand the diagnostic patterns for VOD/SOS in the United States (US) and European Union (EU), a quantitative online survey was conducted among HSCT specialists.MethodsParticipating hematology-oncology specialists for pediatric and adult patients had ≥2 years direct involvement in performing HSCT, spent ≥25% of their time in direct patient care, and managed ≥10 HSCT patients (≥10 allogeneic) in the past year. Their facilities were accredited and performed ≥80 adult HSCT procedures in the US (≥50 in the EU) or ≥20 pediatric HSCT procedures (US or EU). In this survey, VOD/SOS severity was rated as early (milder) or severe (with multi-organ dysfunction). On average, the online survey took 30 to 40 minutes to complete.ResultsSurveys were completed by 100 US physicians (70 adult, 30 pediatric) and 153 EU physicians (122 adult, 31 pediatric; from France, Germany, Italy, Spain, and the United Kingdom). Each physician directly managed an average of 179 (US) or 95 (EU) HSCT patients in the past year. In adult patients, the median percentages of patients treated for severe/early VOD/SOS were 7%/7% in the US and 3%/6% in the EU; in pediatric patients, the median percentages were 9%/12% in the US and 5%/10% in the EU.The most commonly used VOD/SOS diagnostic signs and symptoms (Table) were weight gain and bilirubin level. The median level of weight gain to trigger follow-up action (action not specified but could include further diagnostic testing) was 10% in the US and 5% in the EU, for both adult and pediatric patients; the Baltimore and Seattle criteria specify a weight gain of 5% and 2%, respectively. US physicians were less likely than EU physicians to take action at weight gain of ≤5% (Figure): about half as likely for adults (29% vs 56%) and about a fifth as likely for pediatric patients (14% vs 67%). In addition, at ≤5% weight gain, US physicians of pediatric patients were about twice as likely to take action as US physicians of adult patients. The median bilirubin levels at which US physicians initiated action were 3 mg/dL in adults and 4 mg/dL in pediatric patients, compared with 2 mg/dL for EU physicians in both adult and pediatric patients (Figure); the Baltimore and modified Seattle criteria specify a bilirubin level of 2 mg/dL.ConclusionsThe survey results show that a substantial proportion of US HSCT physicians take follow-up action at weight gain or bilirubin thresholds higher than those in the Baltimore or modified Seattle criteria. Treatment patterns in the EU, particularly among pediatric physicians, appear to be more closely aligned with the diagnostic criteria. The established criteria have limitations; neither set takes into account late onset of VOD/SOS or presentation of edema and weight gain in the absence of other signs and symptoms. As discussed in a recent publication (Mohty M et al. BMT. 2015;50[6]:781-789), elevated bilirubin may be absent in VOD/SOS developing late after HSCT and in children, which prompted the authors to suggest the need for a criteria update.Support: Jazz Pharmaceuticals. Participants received financial remuneration for their survey participation.TableVOD/SOS Assessment Measures Used by PhysiciansBaltimore/Seattle ItemUS(n=95), %EU(n=152), %Weight increaseY5078*Bilirubin increaseY4662*HepatomegalyY3657*AscitesY3649*Ultrasound2747*Liver Doppler2329PainY1629*JaundiceY2528Liver functionY2526Distention/SwellingY2218*P <.05 vs US. [Display omitted] DisclosuresCorn:Jazz Pharmaceuticals: Employment, Equity Ownership. Ogram:Jazz Pharmaceuticals: Employment, Equity Ownership. Doede:Jazz Pharmaceuticals: Employment, Equity Ownership.

Survival Outcomes in Relapsed/Refractory Acute Myeloid Leukemia Patients Who Achieve Less-than-Complete Response After First Salvage Therapy

![Graphic][1] Background Patients with acute myeloid leukemia (AML) who achieve complete remission (CR) after frontline therapy have better outcomes in terms of relapse-free survival and overall survival than those who fail to achieve CR. Patients that achieve complete remission with incomplete platelet recovery (CRp) have an inferior outcome than those with CR, but better than those with no response (Walter et al, JCO 2010). In the setting of relapsed or refractory patients who receive salvage therapy, responses such as CRp and CR with incomplete blood count recovery (CRi) may be seen more frequently. However the clinical benefit of such responses is not known. Aim To evaluate if less-than-complete remissions (CRi) after salvage therapy impact overall survival in relapsed or refractory AML patients when compared to complete remission and no response. Methods We conducted a retrospective analysis of all patients who received salvage therapy (1st and 2nd salvage only) for relapsed or refractory AML at our institution between 2010 and 2012. To assess achievement of response, patients usually have to survive at least 4 weeks as the bone marrow assessment is done at this time. Thus, to adjust for the lead-time bias of patients who achieved any kind of response, only patients who survived at least 4 weeks from the initiation of therapy were included in the analysis. The responses were classified into 3 categories – 1. Complete remission (CR); 2. Incomplete response which includes incomplete blood count recovery (CRi), morphologically leukemia free (MLF), partial response (PR) and 3. No response. Response categories were defined according to the International Working Group response definitions (Cheson et al, 2003). Results During the observation period, 217 patients received 1st or 2nd salvage therapy. Twenty-one of these patients died before 4 weeks after initiation of treatment and were therefore excluded from this analysis. Median age of all patients was 60 years (18-86). 118 patients had received one prior therapy (i.e., 1st salvage group) while 78 had two prior therapies (i.e., 2nd salvage group). Salvage therapy for this analysis was heterogeneous and was classified into hypomethylating agent based therapy in 23 (12%) patients, high-dose cytarabine (>500mg/m2) based regimens in 133 (68%) patients and various investigational regimens in 40 (20%) patients. The last group included investigational new agents or standard agents (other than hypomethylating or cytarabine) being studied in investigational doses or combinations. Prognostic groups based on cytogenetics showed 11(6%), 25(13%), 71(36%) and 76(38%) patients had favorable, intermediate, diploid and adverse cytogenetics, respectively. In 13 (7%) patients, we had insufficient or no sample for cytogenetics. Thirty-five (18%) were FLT3-ITD positive, FLT D835 point mutation was positive in 10 (5%) patients, 2 patients had both ITD and point mutation and FLT3 status was not available in 8(4%) patients; all others were negative. After salvage therapy, 39 (20%) patients achieved CR at some point in their therapy. CRi/PR/MLF was seen in 35 (18%) patients and remaining had no response. Within the CRi/PR/MLF group, the number of patients achieving CRi, MLF and PR were 28, 6 and 1, respectively. The median survival of all patients was 28.4 weeks. Median overall survival for patients in three groups was 79 weeks, 45 weeks and 27 weeks, respectively (p<0.001). Considering only patients receiving 1st salvage therapy, the median survivals for the three groups were 45.6, 41.0 and 28.9 weeks, respectively. Corresponding values for those receiving 2nd salvage were 42.1, 28.1 and 26.7 weeks, respectively. A total of 62(31%) patients received stem cell transplant out of which 47 (24%) had received it after the salvage therapy. Three patients had received two stem cell transplants and salvage therapy was in between the two. The number of patients receiving transplant in three groups (CR, CRi and no response) were 21 (11%), 16(8%) and 13(7%), respectively. Conclusions This analysis suggests that achievement of CRi, MLF or PR in AML patients receiving 1st or 2nd salvage therapy is associated with clinical benefit manifested by improved survival. Although CR still confers the greatest benefit, lesser responses also have a significant impact in survival. ![Figure][2] Disclosures: No relevant conflicts of interest to declare. [1]: /embed/inline-graphic-2.gif [2]: pending:yes

Long-Term Remissions of Patients With Follicular Lymphoma Grade 3 Treated With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP)

Abstract Background Follicular lymphoma grade 3 (FLG3) are recognized as a distinct entity in the World Health Organization classification of lymphoma. FLG3 are defined as > 15 centroblasts per high power field and are further subdivided into A or B on the basis of the presence of centrocytes. Their natural history is similar to that of diffuse large B cell lymphomas (DLBCL) and there is still debate about their optimal management. Methods We conducted a retroprospective analysis of 156 patients with FLG3 receiving frontline treatment at MD Anderson Cancer Center between 06/1973 and 11/2004. Multivariate analysis (MVA) was performed using Hazard Ratio (HR) Cox regression with backward stepwise selection. Logistic regression with odds ratio (OR) was used for MVA of categorical variable. Results Patient baseline characteristics are shown in the Table. Forty-five (29%) patients received R-CHOP, of which 12 (27%) received more than 6 cycles and 9 (20%) and radiation therapy as consolidation. In particular, patients with stage I/II disease (9) all received 5-6 cycles, with additional radiation therapy consolidation in 4 patients. The overall response rate was 100% and 43 (96%) patients achieved complete remission (CR). After a median follow-up of 9 (2-12) years, median PFS has not been reached with 14 (31%) patients relapsing. Nearly all relapses occurred within 3 years, except for 1 patient who relapsed after 8 years and achieved a second durable CR with single agent Rituximab (Figure). On MVA, the only characteristic associated with a shorter PFS was the presence of > 4 nodal sites (HR 4.2, p=0.03). Among relapsed patients, 3 (21%) transformed to DLBCL (1 at first relapse) and died. Six (43%) relapsed patients received stem cell transplant (1 allogeneic) and 5 (36%) received more than 2 salvage regimens. Median OS has not been reached for all R-CHOP treated and relapsed patients. On univariate analysis, the only factor associated with a shorter OS after relapse was transformation (p=0.01). Baseline characteristics associated with transformation on MVA were IPI score 3-4 (OR 1.1, p=0.004) and elevated LDH (OR 2.4, p=0.01). Nine patients died, 2 (22%) of lymphoma progression, 4 (44%) of therapy-related acute myeloid leukemia (AML) and 3 (32%) of cancer-unrelated causes On MVA, factors associated with shorter OS after R-CHOP were age > 60 years (HR 11, p=0.02) and LDH > 618 IU/L (HR 5.9, p=0.01). On univariate analysis, age > 60 years was the only factor associated with AML onset (p=0.04). Table 1 . PATIENTS CHARACTERISTICS (N=45) NUMBER (%) AGE ≥ 60 years 21 (47) MALES 23 (51) ECOG 1-2 1 (2) HISTOLOGY 3B 40 (89) STAGE 3-4 36 (80) NODAL SITES > 4 17 (38) BULKY DISEASE (> 6 cm) 5 (11) EXTRANODAL SITES > 1 6 (13) BONE MARROW INVOLVEMENT 14 (31) B SYMPTOMS 5 (11) IPI 3-4 8 (18) FLIPI 3-5 15 (33) HEMOGLOBIN 8 (18) LDH > 618 IU/L 11 (24) BETA-2-MICROGLOBULIN > 4 mg/L 8 (18) Conclusions R-CHOP is an effective treatment for patients with FLG3 and small number of nodal sites, with rare late progressions. The incidence of transformation is low but is fatal. Onset of second myeloid malignancies is the main cause of death and warrants caution in elderly patients. Disclosures: No relevant conflicts of interest to declare.

Survival Outcomes In Relapsed/Refractory Acute Myeloid Leukemia Patients Who Achieve Less-Than-Complete Response After Salvage Therapy

▪ BackgroundPatients with acute myeloid leukemia (AML) who achieve complete remission (CR) after frontline therapy have better outcomes in terms of relapse-free survival and overall survival than those who fail to achieve CR. Patients that achieve complete remission with incomplete platelet recovery (CRp) have an inferior outcome than those with CR, but better than those with no response (Walter et al, JCO 2010). In the setting of relapsed or refractory patients who receive salvage therapy, responses such as CRp and CR with incomplete blood count recovery (CRi) may be seen more frequently. However the clinical benefit of such responses is not known. AimTo evaluate if less-than-complete remissions (CRi) after salvage therapy impact overall survival in relapsed or refractory AML patients when compared to complete remission and no response. MethodsWe conducted a retrospective analysis of all patients who received salvage therapy (1st and 2nd salvage only) for relapsed or refractory AML at our institution between 2010 and 2012. To assess achievement of response, patients usually have to survive at least 4 weeks as the bone marrow assessment is done at this time. Thus, to adjust for the lead-time bias of patients who achieved any kind of response, only patients who survived at least 4 weeks from the initiation of therapy were included in the analysis. The responses were classified into 3 categories – 1. Complete remission (CR); 2. Incomplete response which includes incomplete blood count recovery (CRi), morphologically leukemia free (MLF), partial response (PR) and 3. No response. Response categories were defined according to the International Working Group response definitions (Cheson et al, 2003). ResultsDuring the observation period, 217 patients received 1st or 2nd salvage therapy. Twenty-one of these patients died before 4 weeks after initiation of treatment and were therefore excluded from this analysis. Median age of all patients was 60 years (18-86). 118 patients had received one prior therapy (i.e., 1st salvage group) while 78 had two prior therapies (i.e., 2nd salvage group). Salvage therapy for this analysis was heterogeneous and was classified into hypomethylating agent based therapy in 23 (12%) patients, high-dose cytarabine (>500mg/m2) based regimens in 133 (68%) patients and various investigational regimens in 40 (20%) patients. The last group included investigational new agents or standard agents (other than hypomethylating or cytarabine) being studied in investigational doses or combinations. Prognostic groups based on cytogenetics showed 11(6%), 25(13%), 71(36%) and 76(38%) patients had favorable, intermediate, diploid and adverse cytogenetics, respectively. In 13 (7%) patients, we had insufficient or no sample for cytogenetics. Thirty-five (18%) were FLT3-ITD positive, FLT D835 point mutation was positive in 10 (5%) patients, 2 patients had both ITD and point mutation and FLT3 status was not available in 8(4%) patients; all others were negative. After salvage therapy, 39 (20%) patients achieved CR at some point in their therapy. CRi/PR/MLF was seen in 35 (18%) patients and remaining had no response. Within the CRi/PR/MLF group, the number of patients achieving CRi, MLF and PR were 28, 6 and 1, respectively. The median survival of all patients was 28.4 weeks. Median overall survival for patients in three groups was 79 weeks, 45 weeks and 27 weeks, respectively (p<0.001). Considering only patients receiving 1st salvage therapy, the median survivals for the three groups were 45.6, 41.0 and 28.9 weeks, respectively. Corresponding values for those receiving 2nd salvage were 42.1, 28.1 and 26.7 weeks, respectively. A total of 62(31%) patients received stem cell transplant out of which 47 (24%) had received it after the salvage therapy. Three patients had received two stem cell transplants and salvage therapy was in between the two. The number of patients receiving transplant in three groups (CR, CRi and no response) were 21 (11%), 16(8%) and 13(7%), respectively. ConclusionsThis analysis suggests that achievement of CRi, MLF or PR in AML patients receiving 1st or 2nd salvage therapy is associated with clinical benefit manifested by improved survival. Although CR still confers the greatest benefit, lesser responses also have a significant impact in survival. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Long-Term Remissions Of Patients With Follicular Lymphoma Grade 3 Treated With Rituximab, Cyclophospamide, Doxorubicine, Vincristine and Prednisone (R-CHOP)

BackgroundFollicular lymphoma grade 3 (FLG3) are recognized as a distinct entity in the World Health Organization classification of lymphoma. FLG3 are defined as > 15 centroblasts per high power field and are further subdivided into A or B on the basis of the presence of centrocytes. Their natural history is similar to that of diffuse large B cell lymphomas (DLBCL) and there is still debate about their optimal management. MethodsWe conducted a retroprospective analysis of 156 patients with FLG3 receiving frontline treatment at MD Anderson Cancer Center between 06/1973 and 11/2004. Multivariate analysis (MVA) was performed using Hazard Ratio (HR) Cox regression with backward stepwise selection. Logistic regression with odds ratio (OR) was used for MVA of categorical variable. ResultsPatient baseline characteristics are shown in the Table. Forty-five (29%) patients received R-CHOP, of which 12 (27%) received more than 6 cycles and 9 (20%) and radiation therapy as consolidation. In particular, patients with stage I/II disease (9) all received 5-6 cycles, with additional radiation therapy consolidation in 4 patients. The overall response rate was 100% and 43 (96%) patients achieved complete remission (CR). After a median follow-up of 9 (2-12) years, median PFS has not been reached with 14 (31%) patients relapsing. Nearly all relapses occurred within 3 years, except for 1 patient who relapsed after 8 years and achieved a second durable CR with single agent Rituximab (Figure). On MVA, the only characteristic associated with a shorter PFS was the presence of > 4 nodal sites (HR 4.2, p=0.03). Among relapsed patients, 3 (21%) transformed to DLBCL (1 at first relapse) and died. Six (43%) relapsed patients received stem cell transplant (1 allogeneic) and 5 (36%) received more than 2 salvage regimens. Median OS has not been reached for all R-CHOP treated and relapsed patients. On univariate analysis, the only factor associated with a shorter OS after relapse was transformation (p=0.01). Baseline characteristics associated with transformation on MVA were IPI score 3-4 (OR 1.1, p=0.004) and elevated LDH (OR 2.4, p=0.01). Nine patients died, 2 (22%) of lymphoma progression, 4 (44%) of therapy-related acute myeloid leukemia (AML) and 3 (32%) of cancer-unrelated causes On MVA, factors associated with shorter OS after R-CHOP were age > 60 years (HR 11, p=0.02) and LDH > 618 IU/L (HR 5.9, p=0.01). On univariate analysis, age > 60 years was the only factor associated with AML onset (p=0.04).Table 1PATIENTS CHARACTERISTICS (N=45)NUMBER (%)AGE ≥ 60 years21 (47)MALES23 (51)ECOG 1-21 (2)HISTOLOGY 3B40 (89)STAGE 3-436 (80)NODAL SITES > 417 (38)BULKY DISEASE (> 6 cm)5 (11)EXTRANODAL SITES > 16 (13)BONE MARROW INVOLVEMENT14 (31)B SYMPTOMS5 (11)IPI 3-48 (18)FLIPI 3-515 (33)HEMOGLOBIN < 12 g/dL8 (18)LDH > 618 IU/L11 (24)BETA-2-MICROGLOBULIN > 4 mg/L8 (18) ConclusionsR-CHOP is an effective treatment for patients with FLG3 and small number of nodal sites, with rare late progressions. The incidence of transformation is low but is fatal. Onset of second myeloid malignancies is the main cause of death and warrants caution in elderly patients.▪ Disclosures:No relevant conflicts of interest to declare.

The impact of RSV, adenovirus, influenza, and parainfluenza infection in pediatric patients receiving stem cell transplant, solid organ transplant, or cancer chemotherapy

RVIs are a significant cause of morbidity and mortality in immunocompromised children. We analyzed the characteristics and outcomes of infection by four respiratory viruses (RSV, adenovirus, influenza, and parainfluenza) treated at a pediatric tertiary care hospital in a retrospective cohort of patients who had received cancer chemotherapy, hematopoietic stem cell, or SOT. A total of 208 infections were studied among 166 unique patients over a time period of 1993-2006 for transplant recipients, and 2000-2005 for patients with cancer. RSV was the most common respiratory virus identified. There were 17 (10% of all patients) deaths overall, of which 12 were at least partly attributed to the presence of a RVI. In multivariate models, LRT symptoms in the absence of upper respiratory symptoms on presentation (OR 10.2 [2.3, 45.7], p = 0.002) and adenoviral infection (OR 3.7 [1.1, 12.6], p = 0.034) were significantly associated with poor outcome, defined as death or disability related to RVI. All of the deaths occurred in patients who had received either solid organ or HSCT. There were no infections resulting in death or disability in the cancer chemotherapy group.

Effects of prophylactic hematopoietic colony stimulating factors on stem cell transplantations: Meta-analysis

Hematopoietic growth factors are often given for prevention of febrile neutropenia (FN), infections, and other complications by hastening neutrophil recovery in the treatment of malignancies after high dose chemotherapy (HDCT). Although several meta-analyses have already demonstrated beneficial effects of prophylactic granulocyte colony-stimulating factors (G-CSF) administration, the effects of G-CSF have not been confirmed in cancer patients receiving stem cell transplantation (SCT) after HDCT. Therefore, we performed a statistical combination of controlled clinical trials to investigate the efficacy of prophylactic use of G-CSF in preventing the neutropenic complications associated with SCT following HDCT in cancer patients. We searched PubMed to identify potentially relevant references and finally selected seven randomized controlled trials that met all of the eligibility criteria. Our meta-analysis demonstrated that prophylactic G-CSF reduced the risk of documented infections and time to hematologic recovery manifested by days to absolute neutrophil count (ANC) ≥ 0.5 × 10(9)/L, days to ANC ≥ 1.0 × 10(9)/L, and days to platelets ≥ 20 × 10(9)/L in SCT patients with cancer following HDCT. The G-CSF treated group also showed a decrease in the length of hospital stay. However, there was no difference between G-CSF treatment group and placebo group in regard to all-cause mortality, infection-related mortality, grade 2∼4 acute graft-versus-host-disease, and episode of fever.

The Effect of Red Ginseng Extract on Inflammatory Cytokines after Chemotherapy in Children

Ginseng has been used as an herbal medicine, widely used in Asian countries, for long time. Recently, beneficial effects for immune functions of Korean red ginseng (KRG) have been reported in adults. This study was performed to investigate the effects of ginseng on immune functions in children after cessation of chemotherapy or stem cell transplantation for advanced cancer. Thirty patients, who were diagnosed and treated for leukemia and solid cancer at the department of pediatrics and adolescence of the Yeungnam University Hospital from June 2004 to June 2009, were enrolled for the study. The study group consisted of 19 patients who received KRG extract (60 mg/kg/d) for 1 yr and 11 patients who did not receive KRG extract were the control group. Blood samples were collected every 6 mo. Immune assays included circulating lymphocyte subpopulation, serum cytokines (IL- 2, IL-10, IL-12, TNF-alpha, and IFN-gamma), and total concentrations of serum IgG, IgA, and IgM subclasses. Age at diagnosis ranged from 2 mo to 15 yr (median 5 yr). Nine patients received stem cell transplantation. The cytokines of the KRG treated group were decreasing more rapidly than that of the control group. Lymphocyte subpopulations (T cell, B cell, NK cell, T4, T8, and T4/ T8 ratio) and serum immunoglobulin subclasses (IgG, IgA, and IgM) did not show significant differences between the study and the control groups. This study suggests that KRG extract might have a stabilizing effect on the inflammatory cytokines in children with cancer after chemotherapy.

Immunonutrition: Does It Have a Role in Improving Recovery in Patients Receiving a Stem Cell Transplant?

Numerous clinical trials have demonstrated that immunomodulating diets (IMDs) reduce treatment complications such as the risk of acquired infections, length of hospital stay, and wound complications in patients receiving planned surgery. These complications are possibly exacerbated by malnutrition at the time of surgery, resulting in decreased cell-mediated and humoral immune responses, which can be improved with the utilization of IMDs both prior to and following surgery. Although numerous randomized studies have investigated IMDs in the surgical setting, IMDs have not been well studied to evaluate whether their use improves outcomes for other patient groups with high incidence of malnutrition and acquired infections. Patients receiving stem cell transplantation following preparative myeloablative chemotherapy for treatment of a hematologic malignancy would be a prime example of another patient group who would share these characteristics. Given the proposed mechanism of action by which IMDs have aided recovery after surgery, it is reasonable to expect that IMDs may aid recovery after stem cell transplantation, and current preclinical and clinical data support the need for further clinical studies.

Natural Killer Cell Mediated Missing-Self Recognition Can Protect Mice from Primary Chronic Myeloid Leukemia In Vivo

BackgroundNatural Killer (NK) cells are thought to protect from residual leukemic cells in patients receiving stem cell transplantation. However, multiple retrospective analyses of patient data have yielded conflicting conclusions regarding a putative role of NK cells and the essential NK cell recognition events mediating a protective effect against leukemia. Further, a NK cell mediated protective effect against primary leukemia in vivo has not been shown directly.Methodology/Principal FindingsHere we addressed whether NK cells have the potential to control chronic myeloid leukemia (CML) arising based on the transplantation of BCR-ABL1 oncogene expressing primary bone marrow precursor cells into lethally irradiated recipient mice. These analyses identified missing-self recognition as the only NK cell-mediated recognition strategy, which is able to significantly protect from the development of CML disease in vivo.ConclusionOur data provide a proof of principle that NK cells can control primary leukemic cells in vivo. Since the presence of NK cells reduced the abundance of leukemia propagating cancer stem cells, the data raise the possibility that NK cell recognition has the potential to cure CML, which may be difficult using small molecule BCR-ABL1 inhibitors. Finally, our findings validate approaches to treat leukemia using antibody-based blockade of self-specific inhibitory MHC class I receptors.

Burden of Illness of FLT-3 Mutated Acute Myeloid Leukemia (AML)

Abstract 4765 Introduction:Patients with FLT3-mutated AML have poor prognoses due to shorter survival, a high incidence of relapse, and a lack of effective treatment options. Limited information is published on the burden of illness (BOI) of AML, especially for patients with FLT3-mutated disease. This study reviewed the epidemiologic, clinical, humanistic, and economic literature and estimated the burden of FLT3-mutated AML in the US. Methods:A systematic literature review was conducted in PubMed to identify clinical and economic publications on AML published in English from 2000 to 2011. Data relevant to the burden of FLT3-mutated AML were abstracted. 607 citations were identified in PubMed. 581 abstracts were screened and 35 articles were abstracted. Epidemiologic data were also sought from the Surveillance, Epidemiology and End Results (SEER) database. Areas where information was limited or not available were identified and discussed with clinicians experienced in treating AML. An Excel model was then developed to estimate the population-level BOI of AML by FLT3 status. Resource utilization estimates were obtained from the literature and expert opinion. Direct costs included procedures, hospitalizations, outpatient/office visits, other resource use (home health care, hospice, skilled nursing facility), and medications (including chemotherapy). Indirect costs included lost productivity but did not include costs associated with premature retirement or premature mortality. Results:In patients age <60 years, the literature reported FLT3 mutations in up to 30% of AML cases. Patients with FLT3-mutated AML have poorer prognoses: per the literature, median overall survival estimates of 15.2–15.5 months for FLT3-mutated AML patients <60 years of age was noted compared to 19.3–28.6 months for wild-type AML patients. Five-year survival rates for age <60 years range from 15% for high ITD-mutant levels to 31% in low ITD mutant-levels for FLT3-mutated AML patients vs. 42% for wild-type AML patients.No studies were identified containing estimates for the incidence or prevalence of FLT-3 mutated AML. The prevalence of AML in 2008 was obtained from SEER data and was estimated at 27,813 patients aged ≥20 years. Age- and gender-specific incidence and relative 5-year survival rates were obtained from SEER data. Projections for the prevalence, incidence, and mortality of FLT3-mutated AML through 2020 were calculated based on the SEER estimates, age- and gender-specific US Census population projections, and an assumption of FLT3 mutations in 23% of AML cases. In 2010, it was estimated that 725 patients aged 20–60 years were diagnosed with FLT3-mutated AML, with 572 disease-related deaths.Three studies were identified which reported information on the impact of AML on quality of life (QoL), though none described the QoL impact of FLT-3 mutated AML. One study specifically examined the <60 year old population, noting that AML patients receiving stem cell transplants had significantly worse long-term impact on QoL vs. patients receiving conventional chemotherapy. No studies quantifying the impact of AML on productivity were identified.In our analysis, the overall economic burden of FLT-3 mutated AML in the US was estimated at $244 million in 2010, including $184 million in direct costs and $60 million in indirect costs from lost productivity. Stem cell transplants accounted for 21% of direct costs, inpatient hospitalizations accounted for 44%, and medications for 4%.For AML patients <60 years, the overall cost per newly diagnosed FLT3-mutated AML patient was estimated at $114,198 vs. $105,825 for newly diagnosed FLT3-wild-type AML patients. This is likely an underestimate of the cost as the impacts of early mortality and early retirement were not included in the indirect costs. In addition, the impact of QoL was not included and this may also underestimate costs due to more frequent use of transplantation in the FLT3-mutated AML population. Conclusions:AML poses a large economic burden, both for the healthcare system and society. FLT3-mutated AML potentially represents a greater per-patient burden than FLT3 wild type AML due to shorter survival rates and use of more costly therapies such as stem cell transplants. Investigational treatments targeting the FLT3 mutation may provide an additional therapeutic option for these patients and have the potential to improve clinical outcomes. Disclosures:Sotak:Novartis: Research Funding. Marin:Novartis: Research Funding. Coombs:Novartis: Employment. Schiller:BMS: Research Funding; Celgene: Research Funding; Ambit: Research Funding; Novartis: Research Funding; Sunesis: Research Funding. Teitelbaum:Novartis: Research Funding.

Conventional Reinduction/Consolidation-Type Therapy Versus Short Course High Intensity Combination Chemotherapy As Post-Induction Treatment for Children with Relapsed Acute Lymphoblastic Leukemia. Early Results of Study ALL-REZ BFM 2002

Abstract 871 Background:Children with relapsed ALL are at a high risk for treatment failure and require improvement of induction and consolidation therapy. Subsequent ALL-REZ BFM trials have been conducted with the aim to define risk factors and to determine adequate intensity and duration of therapy, risk-adapted SCT indication and preventive/therapeutic CNS irradiation. Short course high intensity multiagent chemotherapy elements (R-courses) have been developed as standard of care consolidation therapy of relapsed childhood ALL in countries using ALL-REZ BFM protocols. A conventionally dosed, anthracycline-containing reinduction regimen, termed “Protocol II”, which has resulted in a striking improvement of outcomes in patients with primary ALL treated with BFM protocols, may also be considered as effective consolidation therapy of relapsed childhood ALL.Aim of the study: The multi-centre prospective randomized study ALL-REZ BFM 2002 was designed to compare the efficacy and toxicity of R-courses and Protocol II-Idarubicin (Prot II-IDA) as post-induction therapy in children with relapsed ALL.Patients and methods: A total of 538 children and adolescents aged 1–18 years with first relapse of acute lymphoblastic leukaemia were enrolled in approximately 100 hospitals in Germany, Austria, Switzerland, Czech Republic and Toronto, Canada. 420 patients (78%) were randomized to receive either Prot II-IDA or R-courses as post-induction therapy after uniform induction with F1/2 courses. Further treatment was stratified according to risk groups S1-4: Patients in group S1 (late isolated extramedullary relapse) received 3 more R-courses, local irradiation and maintenance chemotherapy. Patients in group S3/4 (early and very early precursor B cell and any T cell bone marrow relapse) received allogeneic hematopoietic stem cell transplantation (HSCT) from any donor. Patients in group S2 (intermediate risk, all others) were stratified according to the level of minimal residual disease (MRD) in the bone marrow after induction therapy, measured with a PCR-based, centrally reviewed assay: MRD good responders (<10e-3) received 5 additional R-courses followed by maintenance chemotherapy. MRD poor responders (≥10e-3) went on to HSCT from a well matched allogeneic donor. Results:210 patients were allocated to Prot II-IDA course and 210 patients were allocated to R-courses. The randomized groups were well-balanced with respect to relevant clinical parameters including the proportion of patients receiving stem cell transplantation. The estimated 5-year probabilities of event-free survival (pEFS) of the two randomized groups (Prot II-IDA: 0.60 ± 0.04 vs. R-courses: 0.53 ± 0.04, P = 0.30) and overall survival (pOS, Prot II-IDA: 0.69 ± 0.04 vs. R-courses: 0.63 ± 0.04, P = 0.46) were not significantly different. However, the cumulative incidence of subsequent relapse was significantly lower in the Prot II-IDA arm (0.21 ± 0.01) compared to patients treated with R-courses (0.30 ± 0.01, p = 0.03). Treatment-related mortality was mainly associated with HSCT and not different in both arms (0.05 vs. 0.03). Whereas hematological toxicity was higher with Prot II-IDA, more patients suffered from mucositis with R-courses. Conclusion:More than 50% of children with relapsed ALL could be cured with the ALL-REZ BFM 2002 strategy. Post-induction therapy with Protocol II-IDA was associated with fewer subsequent relapses compared to R-courses. Toxicity was acceptable and EFS/OS probabilities were not different in both study arms. Protocol II-IDA will be taken forward as standard post-induction therapy in future ALL-REZ BFM trials. Disclosures:No relevant conflicts of interest to declare.

Future Perspectives: Therapeutic Targeting of Notch Signalling May Become a Strategy in Patients Receiving Stem Cell Transplantation for Hematologic Malignancies

The human Notch system consists of 5 ligands and 4 membrane receptors with promiscuous ligand binding, and Notch-initiated signalling interacts with a wide range of other intracellular pathways. The receptor signalling seems important for regulation of normal and malignant hematopoiesis, development of the cellular immune system, and regulation of immune responses. Several Notch-targeting agents are now being developed, including natural receptor ligands, agonistic and antagonistic antibodies, and inhibitors of intracellular Notch-initiated signalling. Some of these agents are in clinical trials, and several therapeutic strategies seem possible in stem cell recipients: (i) agonists may be used for stem cell expansion and possibly to enhance posttransplant lymphoid reconstitution; (ii) receptor-specific agonists or antagonists can be used for immunomodulation; (iii) Notch targeting may have direct anticancer effects. Although the effects of therapeutic targeting are difficult to predict due to promiscuous ligand binding, targeting of this system may represent an opportunity to achieve combined effects with earlier posttransplant reconstitution, immunomodulation, or direct anticancer effects.