Received Remission Induction Therapy Research Articles

Invasive Fungal Disease in Patients with Myeloid Malignancies: A Retrospective Cohort Study of a Diagnostic-Driven Care Pathway Withholding Mould-Active Prophylaxis

Objectives: Patients receiving remission induction therapy for acute myeloid leukaemia (AML) are at high risk of developing invasive fungal disease (IFD). Newer therapies with targeted antileukemic agents and the emergence of azole resistance pose a challenge to the strategy of primary antifungal prophylaxis. We report the experience of a diagnostic-driven care pathway (DCP) for the management of IFD in these patients, using only culture-directed mould inactive prophylaxis. Methods: Retrospectively, we used a single-centre study of consecutive patients receiving intensive chemotherapy for myeloid malignancies between 2014 and 2021. DCP consisted of serial cultures and serum galactomannan (sGM) screening, CT imaging, and bronchoscopy to direct targeted antifungal treatment. IFD was classified according to the 2020 EORTC/MSGERC criteria. Results: A total of 192 patients with myeloid malignancies received 300 courses of intensive chemotherapy. There were 14 cases of invasive yeast infections and 18 of probable/proven invasive mould disease (IMD). The incidence of probable/proven IMD during the first cycle of remission-induction chemotherapy was 4.6% (n = 9). sGM remained negative in all cases of invasive aspergillosis (IA), with positive mycology findings in bronchoalveolar lavage. All-cause mortality was 9.4% (n = 18) 100 days after starting chemotherapy and was comparable between patients with or without IFD. The fungal-related mortality was 1% (n = 2). Conclusion: Diagnostic-driven based management without universal mould active prophylaxis is a feasible strategy in the management of IFD and limits unnecessary antimould treatment during intensive chemotherapy. The poor performance of serial serum galactomannan screening in detecting IA warrants further investigation.

Association between mortality and cytomegalovirus reactivation during remission induction therapy in patients with rheumatic diseases.

To elucidate the characteristics of patients with rheumatic diseases with cytomegalovirus (CMV) reactivation. In our study, we consecutively reviewed patients with rheumatic diseases who received remission induction therapy in our institution from January 2012 to March 2016 and enrolled the patients who were evaluated about CMV infection. CMV reactivation was characterised by the detection of polymorphonuclear leukocytes with CMV pp65. The characteristics and clinical courses of the patients with CMV reactivation were compared to those without CMV. We observed CMV reactivation in 71 (39.7%, CMV-positive group) out of 179 patients. Age (odds ratio [OR] 1.023, 95% confidence interval [CI] 1.002-1.044, p=0.03), lymphocyte counts (OR 0.999, 95% CI 0.999-1.000, p=0.03), and initial prednisolone dose (OR 18.596, 95% CI 2.399-144.157, p<0.01) were considered as independent relevant risk factors for CMV reactivation. Patients in the CMV-positive group showed significantly higher incidences of all infections (48%) and severe infections (31%) than those in the CMV-negative group (48% vs .31%, p=0.037; 31% vs. 6%, p<0.001, respectively). Higher mortality was observed in the CMV-positive group than in the CMV-negative group (14.1% vs. 1.9%). The lymphocyte counts were more relevant to CMV infection and mortality than were the serum IgG levels. Our study revealed that CMV reactivation occurred in one third of all patients with rheumatic diseases who were undergoing intensive remission induction therapy, and it was found to be relevant to other severe infections and infection-related deaths.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the...

Tacrolimus versus anti-tumor necrosis factor agents for steroid-refractory active ulcerative colitis based on the severity of endoscopic findings: a single-center, open-label cohort study.

Background and aimsAt Saitama Medical Center, for remission induction in active ulcerative colitis (UC) patients with endoscopic evidence of severe disease, we tend to preferentially use tacrolimus (TAC) over anti-tumor necrosis factor (TNF)-α agents. We conducted this study to evaluate the validity of our therapeutic strategies.Patients and methodsThis retrospective study was conducted in 52 steroid-refractory active UC patients with a Clinical Activity Index (CAI) score of ≥7 who were receiving remission induction therapy with TAC or anti-TNF-α agents. The patients were divided into a TAC treatment group (TAC group, n = 29) and an anti-TNF-α agent treatment group (anti-TNF group, n = 23). The CAI, Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and incidence of events (relapse, hospitalization and surgery) were retrospectively analyzed.ResultsAt treatment initiation, the CAI score was 12.6 in the TAC group and 11.5 in the anti-TNF group (P = 0.09), while the corresponding values of the UCEIS were 6.5 and 5.1, respectively (P = 0.0035). The clinical remission rate at 12 weeks was 55% (65% when only the subgroup that received rapid induction therapy was included in the analysis) in the TAC group and 57% in the anti-TNF group, with no significant difference. The cumulative event-free rates at 1, 6 and 12 months were 65.5%, 39.4%, and 39.4%, respectively, in the TAC group and 95.7%, 77.2% and 71.7%, respectively, in the anti-TNF group (P = 0.0037).ConclusionRapid induction therapy with TAC tended to be selected for active UC patients with endoscopic evidence of severe disease, and the present study supported the validity of this therapeutic approach. However, transition to the remission-maintenance phase was more favorable in the anti-TNF group.

Therapy of ANCA-associated vasculitis with severe renal manifestation under routine conditions

In the MEPEX trial the poor prognosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with severe renal manifestation (AAVr) could be significantly improved in the first year by plasmapheresis. How and to what extent is this knowledge of AAVr therapy implemented into routine practice and what effectiveness and adverse events resulted? This was a retrospective cohort study in which all patients who received remission induction therapy for AAVr under routine clinical conditions (RCC) in this hospital from 2009 to 2014 after publication of the MEPEX trial (n= 22) were compared with those in the plasmapheresis arm of the MEPEX trial (n= 70). Endpoints were dialysis-dependent chronic kidney disease and mortality after 3 and 12 months and severe life-threatening adverse events during the first 12 months. All patients with AAVr were treated by plasmapheresis under RCC. The two groups showed no differences with respect to the rate of dialysis dependency (after 3 months RCC 14 % versus MEPEX 16 %, P= 1.00 and after 12 months RCC 23 % versus MEPEX 14 %, P= 0.55) or mortality (after 3 months RCC 18 % versus MEPEX 16 %, P= 0.75 and after 12 months RCC 18 % versus MEPEX 27 %, P= 0.57). The rate of severe life-threatening adverse events was similar under RCC and under controlled study conditions (64 % versus 69 %, P= 0.87). Under RCC there is a high quality of medical treatment for AAVr. All patients received plasmapheresis for remission induction with comparable effectiveness and safety compared to controlled study conditions.

FLAG-Idarubicin Is Superior to Cytarabine Plus Idarubicin (7+3) for Initial Treatment of Acute Myeloid Leukemia (AML): A Multivariable Analysis of Patients Treated at a Single Center

IntroductionCombination chemotherapy with a seven-day continuous infusion of cytarabine (100-200mg/m2/d) plus 3 days of an anthracycline (7+3 ) is considered standard of care for remission induction in newly diagnosed patients with acute myeloid leukemia (AML) However, the MRC AML 15 trial (Burnett et al. J Clin Oncol 2013, 31:3360) suggested that in younger AML patients, a combination regimen containing fludarabine plus intermediate dose cytarabine x 5 days with granulocyte colony-stimulating factor (GCSF) and idarubicin x 3 days (FLAG-Ida) may produce higher CR rates after one course and reduced relapse rates than a combination of cytarabine and daunorubicin given for 3+8 days. The schedule of cytarabine given during DA in the MRC AML 15 trial was not the same as the continuous infusion cytarabine given as standard of care for 3+7 regimens in the United States. We compared standard continuous infusion cytarabine (100mg-200mg/m2/d x 7 days) plus idarubicin (12 mg/m2 /d x 3 days) (AI) administered at our center to FLAG-Ida (fludarabine 25-30mg/m2/d followed 4 hours later by cytarabine (2g/m2/d) x 5 days with granulocyte colony-stimulating factor beginning day 1 until count recovery and idarubicin 10 mg/m2/d x 3 d with respect to safety and efficacy in the initial induction therapy of newly diagnosed AMLMethodsPatients with newly diagnosed AML who received remission induction therapy with FLAG-Ida or AI were identified from January 1 2008 through May 2014. Patients with M3 FAB subtype and those with relapsed or refractory AML were excluded. Supportive care measures were standardized and identical between the two groups. Primary endpoints included complete remission rate post induction therapy, overall survival (OS) and disease free survival (DFS). Remission status was categorized into complete remission (CR), incomplete remission (CRi), and primary induction failure (PIF). Secondary endpoints included non-relapse related mortality (NRM), time to neutrophil recovery >1000 and time to platelet recovery > 100K. CR, CRi and PIF were defined according to the International Working Group recommendations (Cheson B et al. J Clin Oncol 2003 Dec; 21 (24) 4624-49). NRM was defined as death by any cause through day 30 of induction therapy. OS was defined as time from start of therapy to death and DFS was time from diagnosis to relapse or non-relapse death. Subgroups analysis for the primary endpoints were completed based on age (≥60 and <60), and risk status (favorable, intermediate, and poor). Risk status was assessed using molecular and cytogenetic abnormalities defined in the 2014 NCCN guidelines. Cox proportional hazards and logistic regression models were developed for the endpoints using regimen and the other parameters as covariatesResultsWe identified 112 patients who received FLAG-Ida and 56 patients who received AI. Cytogenetic risk and previous antecedent hematologic disorder/secondary leukemia were similar between the two groups. FLAG-Ida achieved faster neutrophil recovery higher overall CR and CR+CRi rate with lower NRM (Table 2). In patients ≥60 years old, CR rates were 75% and 45% for FLAG-Ida vs. AI respectively (p=0.021). OS and DFS between the two regimens did not significantly differ in the subgroup analysis for age or cytogenetic risk group except that intermediate risk patients had better overall survival with FLAG-Ida (p=0.008, log rank test). In a multivariate logistic regression model on achievement of remission (CR+Cri), the use of AI had an odds ratio of 0.38 (p=0.012) compared to FLAG-Ida. In Cox analysis, AI vs FLAG-Ida was a factor of borderline statistical significance for NRM (HR 1.91, p=0.052) and overall survival (HR 1.62, p=0.062)ConclusionsThese data demonstrate faster hematopoietic recovery, superior remission (CR+CR1) and NRM rates for FLAG-Ida when compared to AI. Overall survival rates are confounded by subsequent therapies but also appear to be improved for patients in the intermediate risk group who received FLAG-Ida. Of particular interest was the improvement in CR rates for FLAG-Ida in patients ≥ 60 years of age. These data suggest that FLAG-Ida should be considered a valid option for the initial therapy of AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Benefit of Maintenance Chemotherapy in Patients with Acute Myeloid Leukemia

Background: There is no standard treatment strategy for maintaining first complete remission (CR1) status after several cycles of consolidation chemotherapy in acute myeloid leukemia (AML) patients who are not suitable for transplantation. Maintenance chemotherapy has failed to document the cure rate or prolongation of survivals in patients with acute myeloid leukemia (AML) except for acute promyelocytic leukemia (APL). In this study, we retrospectively compared leukemia free (LFS) and overall survival (OS) of patients with or without maintenance therapy.Methods: Maintenance chemotherapy consisted of daily 6-mercaptopurine and weekly methotrexate per os and lasted for 2 years. Patients who maintained CR1 status after completion of consolidation therapy started maintenance chemotherapy.Results: Fifty two patients (not suitable for transplantation) who completed at least 1 cycle of consolidation therapy were eligible for analysis. Twenty seven patients agreed to administrate oral maintenance chemotherapy whereas 25 patients refused. Median age was 52 years and 24 patients were male. According to the FAB classification, 7.7, 9.6, 40.4, 38.5, 1.9 and 1.9% of patients are AML M0, M1, M2, M4, M6 and M7, respectively. Myelodysplastic syndrome (MDS) related and chemotherapy-related secondary AML patients were 5.6 and 9.6%, respectively. Favorable, intermediate and unfavorable cytogenetic risk groups were 32.7, 63.5 and 2%, respectively. Of 33 patients with intermediate risk, 84.8, 12.1 and 3% were normal karyotype, other not-defined and +8 alone, respectively. Two patients with unfavorable risk were complex karyotype and inv(3). There was no significant difference in the patients’ characteristics between non-maintenance and maintenance group. Almost of all patients (96.4%) received remission induction therapy with a same protocol (7-3 regimen). Relapse was observed in 27 patients (51.9%) after achieving CR1. Median LFS and OS was 28 (95% CI, 2–54) and 29 months (95% CI, 6–52), respectively. The OS was 19 (95% CI, 8–30) and 43 months (95% CI, 19–67) in non-maintenance and maintenance group, respectively (p = 0.044, Fig 1A), whereas LFS was not significantly different. In multivariate analysis, the presence of maintenance therapy was an independent prognostic factor for better LFS (p = 0.044) and OS (p = 0.042, Table 1.). In subgroup analysis (Table 2.)., statistically significant clinical benefit from maintenance chemotherapy was observed in patients with older age (>= 60 years) (p = 0.024), intermediate or unfavorable cytogenetic results (p = 0.004, Fig 1B.), initial higher WBC count (>= 50,000/mm3) (p = 0.005), secondary AML (p = 0.009), and receiving less than 2 cycles of consolidation therapy (p = 0.006).Conclusions: Despite limitation as retrospective analysis with small sample size, our data indicate that maintenance chemotherapy with oral 6-MP and MTX can prolong survivals of patients with AML (except APL) who are not suitable for transplantation as a post-remission therapy particularly with older age, intermediate or unfavorable cytogenetics, initial higher WBC count, secondary AML or receiving less than 2 cycles of consolidation therapy. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Relapsed and secondary disease drive the risk profile for invasive aspergillosis prior to stem cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndrome.

Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) are at risk for invasive aspergillosis (IA) even prior to the introduction of stem cell transplantation (SCT). In times of increasing triazole resistance and changing use of antifungal prophylaxis, insight into the risk factors for IA is needed to improve strategies for preventing IA in this population. Consecutive patients who received remission-induction therapy for AML or MDS at the Leiden Academic Medical Centre were included. Instead of standard antifungal prophylaxis, an assertive protocol for diagnosis of suspected fungal infection was in place. IA was classified according to the revised European Organization for Research and Treatment of Cancer criteria. Potential predisposing characteristics for IA were compared by uni- and multivariate analyses. In 45 (25%) of 184 included episodes (167 patients), IA was diagnosed prior to SCT. A multivariate Cox regression model demonstrated that relapsed AML (hazard ratio [HR] 2.4; 95% confidence interval [CI], 1.1-5.1; P = 0.02), secondary AML (HR, 5.2; 95% CI, 2.3-11.8; P < 0.001), and prolonged duration of neutropenia (HR, 2.2; 95% CI, 1.2-4.0; P = 0.01) were independently associated with IA. Use of granulocyte-colony-stimulating factor showed a trend toward a protective effect (HR, 0.37; 95% CI, 0.1-31.0; P = 0.06). Relapsed AML, secondary AML, and duration of neutropenia were independent factors for determining the risk for development of IA prior to SCT. The results provide further guidance for antifungal stewardship programs when integrating individual patient tailored decision making in antifungal prophylaxis strategies.

Study of the efficacy of mizoribine in lupus nephritis in Chinese patients

We conducted a clinical study in China on the efficacy and safety of mizoribine (MZR) in lupus nephritis. Eleven subjects with proteinuria (≥2 g/day) who had undergone renal biopsy confirming a diagnosis of lupus nephritis (class III: 1 subject; class IV: 6 subjects; class V: 4 subjects) were enrolled. Nine of the subjects were treatment- naive patients who received remission induction therapy, and the other two were switched from cyclophosphamide (CTX) or mycophenolate mofetil due to lack of efficacy. MZR 150 mg was administered once a day. After 6 months, the remission rate was 72.7% (2 subjects achieved complete remission, and 9 partial remission). After 3 and 6 months, significant reductions (p < 0.01) were obtained in 24-h proteinuria (g/day). In the subjects switched to MZR due to lack of efficacy with CTX, the dose was increased from MZR 150-200 mg due to inadequate improvement in proteinuria, and this dose escalation resulted in complete remission after 6 months. It is believed that this kind of dose escalation is one possible treatment option for lupus nephritis. In this study, no adverse events occurred in any of the subjects. We therefore concluded that this first use in China as remission induction therapy in lupus nephritis patients of MZR, which is recognized as an effective maintenance therapy in Japan, was effective. The results also suggest that MZR could be effective in patients for whom other drugs have been insufficiently effective.

Minimal Residual Disease–Guided Treatment Deintensification for Children With Acute Lymphoblastic Leukemia: Results From the Malaysia-Singapore Acute Lymphoblastic Leukemia 2003 Study

To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster-ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10(-3) at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10(-4) at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

Early Diagnostic Procedure and Treatment for Invasive Fungal Infection Centered on Invasive Aspergillosis in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia

Abstract 1544Since myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are more prevalent in the elderly, intensive chemotherapy is difficult. However, recent progress in supportive therapy, especially with anti-fungal agents, and diagnostic procedures for invasive fungal infection (IFI) such as β-D glucan (β-D), galactomannan antigen (GM) and computed tomography (CT), have resulted in dramatically enhanced safety of post-chemotherapy control of elderly patients.To evaluate the efficacy and safety of our diagnosis and treatment strategy for IFI, we examined 112 consecutive episodes in 110 patients who received remission induction therapy from December 15, 2009 to June 18, 2011, including new or recurrent patients with MDS related AML (MDS-AML) and those with AML without a history of invasive aspergillosis (IA). Diagnosis was MDS-AML in 88 episodes (relapse 18) and AML in 24 (M1 5,M2 9,M4 9,M6 1).The median age was 70 (range: 21–88).Remission induction therapy consisted of behenoyl-ara-C for 10 days and idarubicin for 4 days (For further details, please refer to 51st ASH abstract #1052; Taiichi Kyo et al). Patients were always admitted to a clean room until neutrophil recovery, and were routinely administered macrophage-colony stimulating factor (CSF) and granulocyte-CSF. Amphotericin-b syrup and itraconazole capsules were given as antifungal prophylaxis. IFI diagnostic procedures consisted of CT, GM, β-D and surveillance culture (SC). At the time of admission a control CT was taken. CT was repeated within 24 hours when pyrexia of ≥38.0°C occurred. If fever showed no improvement, CT was repeated every 3 days (X-ray was also taken). If any change suggesting infection was noted, treatment against IA was considered. GM, β-D and SC were all conducted twice a week from the time of admission until discharge. ≥0.5 GM was regarded as positive and the treatment against IA was started even if there was only one positive result. At present there is no worldwide consensus concerning β-D, thus we considered a value exceeding the cut-off value of the reagent as positive. Treatment was started when there were both a positive result and increasing fever; and treatment against IA or candidiasis depended on imaging findings. Even if β-D was negative, candida detected by SC or diarrhea combined with increasing fever was also an indication for treatment against candidiasis. IA was treated with voriconazole (VRCZ) and candidiasis with micafungin (MCFG). VRCZ and MCFC were administered at 200–300 mg/twice/day and 100–300 mg/day, respectively. When no sufficient effect was observed with VRCZ alone, MCFG was added.Complete remission (CR) and partial remission (PR) were achieved in 81/112 (72%) and 9/112 (8%) episodes, while in 19/112 (17%) no response was obtained and 3/112 (2.7%) episodes resulted in death during chemotherapy. CR rate was comparable among de novo MDS-AML (49/70, 70%), MDS-AML relapse (9/18, 50%) and AML (23/24, 96%). The cause of death associated with chemotherapy was bacteremia 1, bacteremia or IA 1, and cerebral hemorrhage 1. GM was positive in 48 (43%) episodes. The reason for this large number was probably the advanced age of the patients and the long term neutropenia [absolute neutrophil count <500 (median) 27 days]. In spite of higher IA morbidity, mortality rates seemed very low. Furthermore, although GM >2.5 indicates an unfavorable prognosis and >5.0 no hope of survival, none of our patients with GM >2.5 (10 patients) died of IA (2 died of other causes) and all patients with GM >5.0 (4 patients) survived. Candidemia was found in 2 patients (krusei 1, guilliermondii 1) and were treated succesfully. β-D was positive in 46 /112 (41%) episodes and 28/112 (25%) were also positive for GM. As for GM and β-D, GM positivity preceded that of β-D in 9/28 (32%); regarding GM and CT, GM positivity preceded the observation of CT findings in 13/30 (43%).At the beginning of this study, no control CT was obtained. But in the course of the study we found some patients who presented CT findings indicating IA, such as nodular lesions, but with no infection. Thus, we realized the need for a control CT to detect IA more accurately. Each diagnostic procedure has excellent characteristics but it is not sufficient by itself. The results of this single-center clinical study indicate that an improvement of antifungal therapy combined with a battery of diagnostic procedures may allow safe, intensive chemotherapy for many patients with MDS or AML. Disclosures:No relevant conflicts of interest to declare.

Long-Term Disease-Free Survival of Patients with AML Relapse After T-Cell-Depleted Allogeneic Stem Cell Transplantation by Re-Induction Therapy and Subsequent Interferon-Boosted Donor Lymphocyte Infusion

Abstract 3064Relapse of AML after allogeneic stem cell transplantation (alloSCT) has a very poor prognosis. Salvage re-induction chemotherapy leads to clinical remissions in a substantial number of patients, but these remissions tend to be of short duration. In contrast, donor lymphocyte infusions (DLI) have the potential to effect long-lasting remissions, but the interval of several weeks to months that is required to develop a DLI-induced anti-leukemia response may prevent efficient control of a highly proliferative leukemia. In addition, a high tumor burden may suppress the immune response. In contrast, the combination of efficient cytoreduction by chemotherapy with DLI administered in rapid succession under circumstances favoring the development of an early and profound immune response might have the potential to eradicate otherwise resistant leukemia cells. We therefore adopted an institutional therapeutic strategy for relapsed myeloid leukemia post-allogeneic SCT based on administration of DLI at the anticipated end of the neutropenic phase after salvage re-induction chemotherapy. At this time point, the high prevalence of a pro-inflammatory milieu should favor the induction of the immune response, and an expected state of lymphopenia should promote the expansion of infused T cells by homeostatic proliferation. If 3 weeks after DLI no graft versus host disease (GvHD) was observed, the potential anti-leukemia immune response was further amplified by treatment with interferon- α (IFN- α) until GvHD occurred.Between January 2000 and December 2009 44 patients with relapsed myeloid malignancy after alloSCT were treated at our hospital. Pre-transplant diagnoses were AML n=40, CMML n=1 and MDS n=3. Median time from SCT to relapse was 187 days. Median follow-up after relapse was 3.1 years. 5 patients had a smouldering relapse (<10% bone marrow blasts) and 39 patients had an overt relapse.Of 39 patients with overt relapse, 7 patients (18%) did not receive re-induction therapy due to poor performance status (n=5) or patient choice (n=2). 32 patients received remission-induction therapy consisting of gemtuzumab ozogamycin (n=9), cytosine arabinoside-containing chemotherapy (n=17), or both (n=6). Following this treatment, 7 of 32 patients had rapidly progressive disease during induction therapy (n=6) or died due to toxicity (n=1) and did not receive DLI.The remaining 25 patients received DLI at a dose of 5.0×10 ^6 CD3+ cells/kg for related and 2.5×10 ^6 CD3+ cells/kg for unrelated donors 3 weeks after the start of remission-induction therapy. In 16 of these patients DLI was boosted with IFN- α 3.0×10 ^6 IE once daily. This strategy resulted in acute GvHD in 17 of 25 patients (n=8 grade 1–2, n=9 grade 3–4). At 6 weeks after DLI, 16 patients had reached CR, 5 patients had failed to reach CR (2 with GvHD) and 4 suffered treatment-related mortality (3 with GvHD). Of the 16 patients in CR, 4 had no signs of GvHD and developed a second relapse during the follow-up period. Only 3 of 12 patients in CR with signs of acute GvHD at 6 weeks after DLI developed a second relapse. In total, 9 of 17 patients (53%) with acute GvHD after DLI had long term survival versus none without acute GvHD. During follow-up, 8 patients developed chronic GvHD (n=4 limited, n=4 extensive).Finally, 5 patients with an early detected smouldering relapse received DLI, which was boosted with IFN- α in 2 patients, without salvage re-induction therapy. All 5 patients developed GvHD (n=2 grade 1–2, n=3 grade 3–4) and 3 patients achieved a CR of whom 1 patient died from GvHD.Our results indicate that treatment of relapsed AML after alloSCT with salvage re-induction therapy followed by DLI at the end of the neutropenic phase during minimal residual disease, with additional boosting of the immune response with IFN- α, can result in long-term disease-free survival. Disclosures:Off Label Use: Interferon: DLI-boosting.

Prior Therapy with DNA Methyltransferase Inhibitors (DNMTI) Predicts for Lower Remission Rates and Worse Survival In Secondary Acute Myeloid Leukemia Patients (sAML) Receiving Remission Induction Therapy

AbstractAbstract 4033 Background:DNMTIs are the most commonly used disease modifying agents for myelodysplastic syndromes (MDS), particularly in patients (pts) with higher-risk MDS. Many will subsequently develop acute myeloid leukemia (AML) and will be treated with cytarabine-based remission induction therapy. The clinical impact of prior DNMTI therapy on the effectiveness of AML induction therapy is unknown for pts with AML arising secondary to MDS (sAML). Methods:We reviewed all pts treated with cytarabine-based induction chemotherapy for sAML arising from MDS at Cleveland Clinic between 2002 and 2009, years during which DNMTI therapy may have been used for MDS. Data on demographics, cytogenetic risk classification (per CALGB 8461), and disease duration were collected for MDS and for AML diagnoses. Response to DNMTI therapy (using International Working Group (IWG) 2006 criteria), complete response (CR) to induction chemotherapy (using IWG 2003 AML criteria), and overall survival (OS) were analyzed; comparisons between groups were performed using univariate and regression analyses, controlling for age, gender, white blood cell count, cytogenetics, reinduction, disease duration, and International Prognostic Scoring System (IPSS) score. Results:Of 330 AML pts treated with remission induction chemotherapy over the 7-year period, 27 had an antecedent MDS; 14 were treated with DNMTI prior to AML transformation, 13 were not. For these sAML pts, mean age was 67.5 years (range, 39–85), 11 (41%) were female, AML cytogenetic risk groups were intermediate (13), poor (10), and unknown (4), while IPSS cytogenetic risk groups were good (12), intermediate (7), poor (3), and unknown (5). Only 2 pts (7%) had a chromosome 7 abnormality. By MDS WHO classification, pts had RA/RARS (4), RCMD (6), RAEB-1 (6), RAEB-2 (9), and CMML-1 (2). Pts had MDS a median of 1.76 years (range .33-6.0). Compared to pts not treated with DNMTI, pts who received a DNMTI for MDS were younger (63 vs. 72 years, p=.013) but duration from MDS diagnosis to AML diagnosis was similar between groups (1.6 years vs 1.9 years, p=.60), as were other baseline factors identified above. Among sAML pts, reinduction rate for persistent leukemia was qualitatively higher in the DNMTI group (36% vs 8%), with a trend towards significance (p=.08). CR to AML induction for the sAML pts was 41% (compared to 52% for all AML patients ≥60 years who were induced), but was significantly worse in the DNMTI group (21% vs 62% for non-DNMTI, p=.034), and by log rank there was a trend toward worse OS in those treated with a DNMTI (.5 years vs 1.1 years, p=.11, similar to all AML patients ≥60 years, at .41 years). When compared to sAML without prior DNMTI, by logistic regression analyses, prior use of a DNMTI led to a worse CR rate to induction (hazard ratio .026, p=.047), and using Cox regression, prior use of a DNMTI led to worse OS (hazard ratio 22.95, p=.004). Within the MDS group treated with a DNMTI, achievement of complete or partial response by IWG MDS criteria was significantly correlated with CR to induction chemotherapy for AML (Pearson correlation coefficient .61, p=.021) but not with OS (Pearson correlation coefficient .40, p=.15). Conclusions:Induction therapy in sAML pts previously treated with DNMTI for MDS is less effective and associated with worse OS when compared to sAML pts not treated with DNMTI, controlling for baseline factors including MDS duration and IPSS score. However, within this poor-risk group, clinical response to DNMTI therapy is correlated with improved CR to AML induction therapy. Treatment alternatives to induction chemotherapy for AML after prior DNMTI therapy should be investigated. Disclosures:Mohan:Celgene: Research Funding; Eisai: Research Funding. Maciejewski:Celgene: Research Funding; Eisai: Research Funding. Sekeres:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. [Display omitted]

Over-Expression of Novel IRF8 Splice Variants Is Associated with a Significant Decrease In Relapse-Free Survival In Adult AML Patients.

AbstractAbstract 1679 Introduction:Aberrant expression of the wild-type transcript of interferon regulatory factor 8 (IRF8-WT) in hematopoietic stem cells is associated with differentiation block, inhibition of apoptosis, and leukemogenesis. We recently identified 3 novel transcript variants of IRF8 (IRF8-SVs). Each of the splice variants introduces a part of the terminal portion of intron 1 into the transcript, while splicing out exon 1 of the reference sequence (data submitted in a separate ASH abstract). Although these splice variants can be found at very low levels in hematopoietic cells from “healthy” adults, we have found that a subpopulation of AML patients expresses IRF8-SVs at much higher levels (>2-fold) than hematopoietic cells from normal donors. Therefore, we performed a retrospective study to examine the prognostic significance of IRF8-SV transcripts in previously untreated adult AML patients. Methods:RNA from pretreatment bone marrow (BM) or peripheral blood (PB) was available in the Southwest Oncology Group (SWOG) repository for 194 patients with previously untreated AML. These patients received remission induction therapy with cytarabine and daunorubicin on SWOG trials S9031, S9126, S9333, or S9500. Compared to the other patients on these trials, the 194 patients had higher WBC counts (median 32,100/mcL vs. 7,300/mcL), BM and PB blast percentages (medians 70% vs. 60% and 44% vs. 20%, respectively) and were younger (median 61 vs. 66 years), more likely to have normal karyotype (44% vs. 34%), and less likely to have deletions of chromosomes 5q and/or 7q (11% vs. 25%). After adjusting for these factors, the 194 patients did not differ significantly in complete response (CR) or resistant disease (RD) rates, relapse-free survival (RFS), or overall survival (OS) from other trial participants. Quantitative RT/PCR (Q-RT/PCR) assays were developed to specifically quantify the collective expression of the three IRF8-SV transcripts. B-glucoronidase (GUSB) was used as endogenous control to correct for RNA integrity. Fold change was computed relative to the pool of RNA from the peripheral blood of 10 healthy donors using the 2-ΔΔCt method. All Q-RT/PCR assays were performed in duplicate with appropriate negative and positive controls. Geometric means of the duplicate fold-change values were used for all statistical analyses. Results:Increased IRF8-SVs expression (defined by >2-fold change) was present in 26 patients (13%) and was significantly associated with higher CD34 expression (P<0.0001), but not with WBC, blast percentages (BM or PB), normal karyotype, or FLT3 ITD. Patients with increased IRF8-SVs expression had lower CR rate (23% vs. 52%, P=0.010), higher RD rate (54% vs. 31%, P=0.044), reduced OS (hazard ratio [HR] = 1.41, P=0.14) and poorer RFS (HR=3.01, P=0.029). After adjusting for effects of age and CD34 expression, increased IRF8-SVs expression was significantly associated with poorer RFS (HR=2.94, P=0.015, Figure 1), but not with CR (odds ratio [OR] = 0.54, P=0.26), RD (OR=1.58, P=0.34) or OS (HR=1.00, P=1.00). Conclusions:This is the first study examining the clinical importance of these novel IRF8 splice variants in malignant cells. We found that increased expression of IRF8-SVs was associated with a low CR rate and significantly inferior RFS in adult AML patients, suggesting that IRF8-SVs may be a novel and important AML prognostic biomarker. Additional studies are planned to examine the clinical and functional significance of the three novel IRF8 splice variants, individually and collectively, in a larger AML population and other hematopoietic malignancies. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Wegener's granulomatosis in which rheumatoid factor was useful for evaluating the disease status: a case report

IntroductionAccurate evaluation of disease status is very important in treatment of Wegener's granulomatosisCase presentationA 73-year-old Japanese man presented with chronic sinusitis and otitis media. He was admitted to our hospital because of bilateral lung nodules. Cytoplasmic antineutrophil cytoplasmic antibody was negative but his rheumatoid factor was high. He was diagnosed with limited Wegener's granulomatosis and received remission induction therapy. His serum rheumatoid factor level correlated with the Wegener's granulomatosis state when he experienced a severe infection and recurrence due to Wegener's granulomatosis.ConclusionWe describe a case of Wegener's granulomatosis in which rheumatoid factor was helpful for evaluating the therapeutic effect.

Clinical Significance of PML/RAR Isoform in Patients of Acute Promyelocytic Leukemia.

Background: Three types of PML-RARα mRNA fusion transcripts in acute promyelocytic leukemia (APL) could be existed: a short (S)-form type, a long (L)-form type or a variable (V)-form type. Whether 3 types of PML-RARα mRNA fusion transcripts associated with different manifestations and outcomes in individual APL cases are unclear. Recently, some studies reported the controversial results for the relationship between the types of PML-RARα mRNA fusion transcripts and clinical outcomes. But, there was no data about the types of PML-RARα mRNA fusion transcripts especially for the APL patients who were received remission induction therapy with AIDA.Methods: We performed a retrospective analysis for the data of 94 patients with APL, whose isoform data was available. We evaluated the differences of therapeutic outcome of remission induction chemotherapy in terms of response rate, relapse-free survival (RFS), overall survival (OS) and the association of pretreatment clinical parameter characteristics according to the PML-RARα isoforms.Results: The median age of the patients was 41 years (15–85). CR rate following remission induction treatment was 84.9% (AIDA 87.0% vs. non-AIDA 80.0%). Among 94 patients, there were 58 L-form cases (62.1%), 32 S-form cases (34.0%), 4 V-form cases (4.3%). There was no significant difference at any patient's pretreatment characteristic according to PML-RARα isoform type. CR rate was higher in the group of initial WBC <10,000/ul (93.5% vs. 65.4%, p=0.001). But there was no difference within the isoform L/S subgroup (84.2% vs. 87.2%). And OS and RFS were not different between isoform L/S subgroup (5yr 74.3% vs. 83.1%, 84.2% vs. 85.1%). AIDA induction group was better than non-AIDA induction group regarding OS and RFS (5yr 84.4% vs 55.7%, p=0.026, 90.0% vs 65.7%, p=0.007), but not significant in the multivariate analysis. And also, it was not significantly different in the OS and RFS between isoform L/S subgroup of the AIDA induction group (5yr 80.5% vs. 92.0%, 95.7% vs. 97.0%).Conclusion: This study suggests that1.high initial WBC count is associated with low CR rate,2.AIDA induction group has a trend of better OS and RFS,3.treatment outcomes according to PML-RARα isoform type are not different.Prospective study will be needed to confirm the meaningful significance of PML-RARα isoform type.

Impact of socioeconomic status and distance from treatment center on survival in patients receiving remission induction therapy for newly diagnosed acute myeloid leukemia

Background While socioeconomic status (SES) and the distance patients travel to a treatment center (DTC) impact survival of certain solid tumors, little is known of their influence in acute myeloid leukemia (AML). Methods We retrospectively reviewed patients receiving remission induction therapy for AML at the Cleveland Clinic between January 1997 and December 2005. Demographic data were obtained from medical records. Income and DTC were determined using online databases . Known prognostic factors (age, WBC count at diagnosis, cytogenetics, AML etiology) were collected and controlled for in Cox proportional hazards analysis. Results Induction chemotherapy was administered to 281 patients; 91% were Caucasian (C), 8% were African American (AA), and 1% were neither (non-AA non-C). The median DTC was 24 miles (range, 0.9–2058), and median annual household income was $38,972 (range, $17,496–143,220). With a median follow up of 22.6 months, the median overall survival (OS) was 11.3 months. In multivariable analyses, age ≥60 years, unfavorable cytogenetics, initial WBC count and secondary AML significantly influenced survival ( p < 0.001, p < 0.001, p = 0.035, and p = 0.010, respectively). OS was similar for AAs and non-AA non-Cs compared to Cs (HR = 1.12, 95% CI = .61–2.07, p = .71, and HR = 0.87, CI = 0.21–3.62, p = .84, respectively). Neither DTC (HR = 1.00, 95%CI = 0.98–1.01, p = .96 per 20 mile increment) nor SES (HR = 1.02, 95%CI = 0.92–1.13, p = .77 per $10000 annual income increase) had an impact on OS. Conclusion Unlike with many solid tumors, SES and DTC are not predictive of outcome in AML patients.

Impact of Socioeconomic Status and Distance from Treatment Center on Survival in Patients Receiving Remission Induction Therapy for Newly Diagnosed Acute Myelogenous Leukemia (AML).

Background: Socioeconomic status (SES) and distance from a treatment center are prognostic factors in chronic malignancies, such as head and neck or breast cancer, where relative disease latency enables patients with greater means to travel to receive their care. Little is known about the influence of these demographics on patient outcomes in rapidly-growing cancers, such as AML.Methods: We conducted a retrospective review of all patients receiving remission induction therapy for AML at the Cleveland Clinic between January 1997 and December 2005. Race and residential zipcodes were obtained from information disclosed by patients in their electronic medical records. Average annual household income in a zipcode and distance from the treatment center were obtained using web-based databases (www.melissadata.com, www.zip-codes.com). Data on known prognostic factors (age, WBC at diagnosis, cytogenetic risk groups (as defined by CALGB 8461) and AML etiology (de novo vs. secondary AML)) were collected and controlled for in multivariable analyses. Survival was estimated using the Kaplan-Meier method, and the association between distance and income assessed using the Spearman rank correlation.Results: Anthracycline-based remission induction chemotherapy was administered to 281 patients: 132 (47%) were female, with a median age at diagnosis of 60 years (range 17–80). Median WBC at diagnosis was 9.9 k/uL (range:0.4–550 k/uL). Cytogenetics were favorable in 33 patients (11.7%, 10 of whom had t(15;17)), intermediate in 137 (48.8%), unfavorable in 73 (26%), and unknown in 38 (13.5%). Ninety patients (32%) had secondary AML. The ethnic distribution was consistent with other AML series: 252 (90.6%) were Caucasian (C), 22 (7.9%) were African American (AA), and 4 (1.4%) were neither (non-AA non-C). The median distance from the treatment center was 24.4 miles (range: 0.9–2058), and median average household income was $38,972 (range: $17,496-$143,220). Overall survival (OS) was 30.2% at a median of 22.6 months of follow-up. There was no significant correlation between distance and income. In both univariable and multivariable analyses, age ≥60 years, unfavorable cytogenetics, increased WBC count at presentation and secondary AML were all found to adversely affect survival (p<0.001, p<0.001, p=0.035, and p=0.010, respectively). OS was similar for AA and non-AA non-C patients compared to C (HR=1.12 [95% CI=.61–2.07, p=.71], and HR=.87 [CI=.21–3.62, p=.84], respectively). Neither distance from treatment facility (HR=1.00 [95%CI = .98–1.02 p =.96] for every 20 mile increase in distance) nor SES (HR=1.02 [95%CI=.92–1.13, p=.77] per $10000 increase) had an impact on OS. Similar findings held for CR rates.Conclusion: Contrary to their impact on chronic malignancies, neither SES nor distance from treatment facility affect outcome in patients with AML treated at the same hospital. This supports referring patients for treatment to tertiary facilities skilled at managing AML, even when they live at great distances from those facilities.

Outcome of Patients with Secondary Leukemias Managed with Different Treatment Strategies at a Single Center.

134 patients with a prior diagnosis of a malignant solid tumor presented between 1 Jan 95 and 31 Dec 04 to the leukemia service at PMH for management of a secondary hemopoietic malignancy or aplasia (AML n=99, MDS n=22, ALL n=11, AA n=2). The cohort included 65 males (median age 70 years, ranging from 18–94 years) and 69 females (median age 60 years, ranging from 25–87 years). The tumor types showed the expected gender based variation. Based on age, performance status and patient preference 81 individuals received remission induction therapy, while 53 patients were managed with supportive care. 49 of the patients undergoing induction therapy met the age criteria (70 years) for a blood and marrow transplant (BMT) and survived at least 70 days post initiation of induction therapy. 25 of the 49 patients underwent allogeneic BMT from related (n=20) or unrelated donors (n=5). The median survival of all 134 patients amounted to 314 days with an overall survival (OS) at 2 and 3 years of 25% and 20%. The respective values for patients undergoing induction therapy and supportive care were 413 days,36%,28% and 192 days, 9%,7% (p= 0.0002). Survival was strongly influenced by age (p= 0.0017), while gender (p=0.1436) and FAB subtype (p=0.219) did not contribute significantly to outcome. Subset analysis of the 25 BMT recipients showed a median survival of 922 days, with a 51% and 39.5 % OS at 2 and 3 years. The respective data for the remaining 24 not transplanted patients were not significantly different (p= 0.7508) with 522 days, 42% and 35%. Both subgroups however differed significantly in their causes of death favoring a lower relapse rate for transplant recipients and lower treatment related mortality (TRM) for non-transplanted patients (p=0.0012). In conclusion, this single center study confirms the relatively poor outcome for patients with secondary leukemias but is consistent with the view that patients able to undergo intensive therapy including transplantation may derive a significant survival benefit. The low relapse rate observed for BMT patients compared to patients not transplanted may translate into a survival benefit provided TRM can be reduced

Allogeneic (Allo-) or Autologous (Auto-) Peripheral Blood Stem Cell Transplantation (SCT) Randomized Versus a Second Intensive Consolidation after a Common Induction and Consolidation Course in Patients with Bad Prognosis Myelodysplastic Syndromes and Acute Myelogenous Leukemia Following MDS of More Than 6 Months Duration: The Final Analysis of a Joint Study (CRIANT) of the EORTC, EBMT, SAKK, HOVON and GIMEMA Leukemia

Allo-SCT is currently considered the only curative treatment option of patients (pts) with advanced stages of MDS. The CRIANT study tested in pts without an HLA-id. sibling the value of auto-SCT versus one additional course of high dose cytarabine (HDAC). Pts with identified HLA-id. sibling(s) were candidates for allo-SCT. All pts received remission-induction therapy consisting of idarubicin, cytarabine and etoposide (ICE). Pts who reached CR received one consolidation course (cons) with intermediate dose of cytarabine and idarubicin. All pts without a HLA-id. sibling received filgrastim during the recovery phase of 1st cons to mobilize stem cells and were randomized between ASCT and 2nd cons. Between November 1996 and September 2003, 345 pts were registered (69% of them ≤ 55 years of age and 77% with MDS). Reviewed cytogenetic data were available of 295 (86%) and FISH data of 167 pts (48%). Out of 341 evaluable pts 256 have died and the median follow-up was 5.3 years. The median survival was 1.3 years and the 4-year survival rate was 29% (SE=3%). Age (> vs ≤ 55 yrs: HR=1.5, p=0.003) and the IPSS cytogenetic/FISH score (intermediate vs low: HR=1.5, p=0.02; high vs low: HR=3.1, p<0.0001) were independent prognostic factors for survival. ICE induced CR in 194 (57%) pts. The median DFS was 1.0 yr and the 4-year DFS rate was 29% (SE=3%). 176 (91%) CR pts received the 1st cons. 34 pts were randomized for auto-SCT and 38 for HDAC. Mobilization of stem cells after the 1st cons was adequate in 48 and failed in 54 pts. In total 19 randomized pts (56%) received auto-SCT and 26 (68%) received HDAC. The 4-year DFS rates of the 2 groups were 30% (SE=8%) and 17% (SE=7%), resp. (p=0.32). The 4-year DFS rate of pts with a failed mobilization was 26% vs 17% for those with a successful harvest (p=0.21; p=0.76 adjusted for cytogenetics). The outcome of pts in CR (≤ 55 yrs) was compared according to the availability of a HLA-id. sibling donor. The 4-year DFS of the 50 pts with a donor was 45% (SE=8%) and of the 85 pts without a donor 27% (SE=7%) (HR=0.62, 95% CI 0.39–0.97, p=0.04, after adjustment for age and IPSS cytogenetic score). In intermediate/high risk pts. the difference was higher (HR=0.43, p=0.009). Cytogenetic analysis in CR was performed in 43 of 73 pts in CR with cytogenetic/FISH aberrations at diagnosis. The 4-year relapse rate was higher in the 13 pts with persisting abnormalities compared to the 30 pts with no cytogenetic abnormalities in CR: 93% versus 74%, resp. (p=0.22). In conclusion: cytogenetic characteristics and age are the major prognostic factors in MDS/sAML pts treated by intensive remission-induction/consolidation chemotherapy, followed by another consolidation course or SCT. Pts with a donor and candidates for allo-SCT in CR-1 have a better outcome than those without a donor. Pts randomized for auto-SCT had a 13% higher 4-yr DFS rate than those randomized for intensive chemotherapy only.