Early Intensification Of Therapy Research Articles

Utilization of metastatic hormone sensitive prostate cancer (mHSPC) treatment in a community oncology practice setting.

86 Background: Treatment options for mHSPC have continued to evolve. While androgen deprivation therapy (ADT) has been the backbone treatment, more recently early use of docetaxel and/or novel androgen receptor inhibitors (nARIs) has demonstrated improved clinical outcomes. This study assessed real-world treatment among mHSPC patients who received at least one line of therapy (LoT). Methods: A retrospective observational study utilizing de-identified health records from five Cancer Treatment Centers of America (CTCA) included patients with metastatic prostate cancer who were treated with ADT, docetaxel or nARIs at CTCA for 6+ months between 1/2015-3/2021. Treatment patterns were observed from first LoT to metastatic castration resistance, death, or lost-to-follow-up until 3/2022. LoT was defined as first to last date of active drug therapy, not including long-term hormone agonists. First LoT was defined as initial regimen with no new drugs added 30+ days after start date. Patient characteristics, proportion and duration of each LoT, and reasons for early discontinuation were gathered using structured data elements and chart abstraction. Results: The characteristics of the 523 patients in this study were as follows: mean (SD) age 62 (8) years, 60% white and 33% black, 53% with commercial insurance, 75% with ECOG 0-1, and 65% with bone metastasis at diagnosis. Median follow-up time was 2.9 years. The most common LoT 1 regimen was either ADT alone or ADT with first generation androgen receptor inhibitors (FGARI) (table below). 46% received a second and 15% received a third LoT. Mean (SD) duration of first and second active LoTs were 12 (11.8) and 10 (11.1) months, respectively. Among the 65% and 78% patients who discontinued therapy in LoT 1 and 2, respectively, the majority discontinued due to progression of disease (35% LoT 1 and 53% LoT 2) followed by patient choice (23% LoT 1 and 18% LoT 2). Conclusions: Despite recommendations from guidelines on early intensification of therapy in mHSPC, in this contemporary cohort we find that most patients received either ADT alone or ADT ± FGARI in LoT 1 while chemotherapy and nARIs were initiated predominantly in later lines. Most patients discontinued LoT 1 due to disease progression which may suggest undertreatment and need for improved outcomes. Further studies are needed to assess the factors associated with non-intensification of treatments. [Table: see text]

Long-term Outcomes Among Young Adults With Type 2 Diabetes Based on Durability of Glycemic Control: Results From the TODAY Cohort Study.

To examine the effect of different patterns of durable glycemic control on the development of comorbidities among youth with type 2 diabetes (T2D) and to assess the impact of fasting glucose (FG) variability on the clinical course of T2D. From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 457 participants (mean age, 14 years) with mean diabetes duration <2 years at entry and a minimum study follow-up of 10 years were included in these analyses. HbA1c, FG concentrations, and β-cell function estimates from oral glucose tolerance tests were measured longitudinally. Prevalence of comorbidities by glycemic control status after 10 years in the TODAY study was assessed. Higher baseline HbA1c concentration, lower β-cell function, and maternal history of diabetes were strongly associated with loss of glycemic control in youth with T2D. Higher cumulative HbA1c concentration over 4 years and greater FG variability over a year within 3 years of diagnosis were related to higher prevalence of dyslipidemia, nephropathy, and retinopathy progression over the subsequent 10 years. A coefficient of variability in FG ≥8.3% predicted future loss of glycemic control and development of comorbidities. Higher baseline HbA1c concentration and FG variability during year 1 accurately predicted youth with T2D who will experience metabolic decompensation and comorbidities. These values may be useful tools for clinicians when considering early intensification of therapy.

IDF21-0400 Cross-sectional ObservaTional Study to assess Effectiveness, Safety of VildaglIptin/ MetfOrmin In T2D Patients – ACTION

Background: The high burden of T2D in South East Asians has been debated on several mechanisms including reduced beta cell function, impaired insulin resistance owing to low oxidative skeletal fibre mass and/or ectopic fat deposition making the choice of DPP-4/Biguanide, a relevant combination especially in Indian settings. In addition, the treatment challenges on physician and patient inertia often alludes for complimentary strategies to reduce pill burden while complying with International recommendations on target goals especially with early intensification of therapy as highlighted by AACE.

Alfa-feto protein (AFP) as a predictor of outcome for children with germ cell tumors: A report from the malignant germ cell international consortium.

10036 Background: There are several studies describing the correlation between unsatisfactory tumor marker decline and poor prognosis in adult patients treated for germ cell tumors. In pediatric patients the data is limited. We therefore retrospectively analyzed data collected from pediatric patients treated on the Children’s Oncology Group (COG) Protocol AGCT0132 to determine whether a relationship exists between AFP decline and outcome. Methods: One hundred and thirty-one patients with germ cell tumors enrolled on Children’s Oncology Group Protocol AGCT0132 were eligible for analysis of AFP decline. Serum AFP half-life was calculated from levels collected post-operatively and after the start of chemotherapy, excluding values in the first 7 days of chemotherapy to accommodate unpredictable increases in the initial days of treatment. AFP decline was defined as automatically satisfactory (AFP normalized within the first two AFP measures following the start of chemotherapy), calculated satisfactory (AFP half-life ≤7 days following the start of chemotherapy), and unsatisfactory. Results: The 3-year event-free survival (EFS) was 87 % (95% confidence interval-CI: 79-92 %) for patients with a satisfactory decline and 62 % (95% CI: 31-82 %) for patients with an unsatisfactory decline (p = 0.006). In stratified analyses, this effect was limited to patients ≥11 years of age and with standard risk (SR2) disease ((p = 0.002 and p = 0.004, respectively). Three-year overall survival for patients with satisfactory versus unsatisfactory decline was not statistically significant. Conclusions: This study is the first to show an association between AFP decline and EFS in pediatric patients. Although there is no statistically significant association between tumor marker decline and overall survival, recognition of patients at high-risk of relapse may allow for early intensification of therapy and impact the rationale for future clinical trial design.

Favourable outcomes of poor prognosis diffuse large B-cell lymphoma patients treated with dose-dense Rituximab, high-dose Methotrexate and six cycles of CHOP-14 compared to first-line autologous transplantation.

The optimal therapeutic approach for young diffuse large B-cell lymphoma (DLBCL) patients with high-intermediate and high-risk age-adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10-year single-centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R-CHOP-21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21days) followed by first-line high-dose chemotherapy with autologous stem-cell support (HDCT-ASCT), resulting in 2-year progression-free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP-14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14days) with dose-dense rituximab and high-dose methotrexate resulting in promising overall response- (93·3%) and complete remission (90%) rates and sustained survival (2-year PFS and OS: 93·3%). In an intention-to-treat analysis, 2-year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P=0·009) and OS (69·7% vs. 93·3%, HR 4·95, P=0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox-regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83-35·9, P=0·006) and OS (HR 5·86, 95% CI 1·28-26·8, P=0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor-prognosis DLBCL patients appears superior after early therapy intensification.

Role of Positron Emission Tomography (PET/CT) in Primary Mediastinal Large B Cell Lymphoma (PMLBCL): Preliminary Results of an International Phase II Trial (IELSG-26 Study) Conducted On Behalf of the International Extranodal Lymphoma Study Group (IELSG), the Fondazione Italiana Linfomi (FIL) and the UK NCRI Lymphoma Group

AbstractAbstract 1566 Background.Response-tailored management of PMLBCL is a major challenge in everyday practice, mostly due to the persistence of post-treatment residual masses of uncertain nature. PET/CT is now widely used in the definition of response and as a prognostic indicator, in Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL), while its role in patients with PMLBCL remains to be defined. Aim of the study.The IELSG-26 study was designed to prospectively evaluate the clinical role of PET/CT after rituximab and anthracycline-containing immunochemotherapy (R-CHT) in patients with PMLBCL. Methods.Between January 2007 and July 2010, 125 patients (pts) with PMLBCL were enrolled in 21 institutions and treated with R-CHOP-like (20 pts), R-VACOP-B (34 pts) or R-MACOP-B (71 pts) regimens according to the local policy; consolidation with mediastinal involved field radiotherapy (IFRT) as indicated by local guidelines was allowed. PET/CT scans were planned at baseline, at 3–4 weeks after R-CHT and at 12 weeks after radiotherapy. Central PET/CT review was performed at the end of treatment using the Deauville score (Meignan et al. Leuk Lymphoma 2009) and complete response (CR) was defined as a negative PET scan or one having minimal residual uptake lower than mediastinal blood pool (MBP) activity in regions which were FDG-PET positive at baseline according to the criteria of the International Harmonization Project in Lymphoma (Juweid et al. JCO 2007). Results.Treatment was administered as initially planned in 119 pts (including IFRT in 106); there were 6 early withdrawals (4 with early progression and 2 with stable disease receiving second-line chemotherapy). PET imaging was not done (n=2) or not evaluable due to technical problems (n=2) in 4 pts, therefore, central review of PET/CT was possible in 115/119 patients. PET/CT visual assessment at 3–4 weeks post-R-CHT showed metabolic CR in 54/115 patients (47%; 95% CI, 36%–56%): in 12 cases (10%; 95% CI, 6%–18%) PET/CT scan was completely negative (score 1 according to the Deauville criteria), while in 42 (37%; 95% CI, 28%–46%) there were small residual masses with an uptake less than MBP (score 2). PET/CT scans showed a positive residual mass after R-CHT in 61/115 pts (53%; 95% CI, 44%–62%). The residual uptake was higher than MBP but below the liver uptake (score 3) in 27 pts (23%; 95% CI, 16%–32%), slightly higher than the liver uptake (score 4) in 24 pts (21%; 95% CI, 14%–29%) and markedly higher than the liver uptake (score 5) in 10 pts (9%; 95% CI, 4%–15%). Despite only 47% of patients attaining a CR -defined by the uptake below MBP activity- after R-CHT, at a median follow-up of 2.8 years, the estimated 5-year overall survival (OS) and progression-free survival (PFS) rates were 96% (95% CI, 89%–98%) and 91% (95% CI, 84%–95%), respectively. The achievement of a CR at 3–4 weeks after R-CHT predicted a longer PFS (p=0.015) with high sensitivity but poor specificity (negative predictive value of 0.98 but positive predictive value of only 0.15) and showed a borderline impact (p=0.052) on OS. Patients with Deauville score 3 had a clinical outcome identical to that of ‘PET negative' (score 1–2) pts and ROC analysis suggested that moving the cut-point for the definition of CR from the MBP to the liver uptake, will increase specificity while maintaining sensitivity. Indeed, defining the response using the liver uptake as a cutpoint is a better predictor for both PFS (p<0.001) and OS (p=0.001); of 10 pts with disease progression, 9 had score 4–5 and one score 2. The latter was one of the five pts with score 1–3 who were not irradiated. All the 4 recorded deaths occurred in the group of patients with score 4–5. Conclusions.Using the MBP cut-point, the PET-positive rate (Deauville score>2) after R-CHT in PMLBCL was higher (53%) than in DLBCL. However, more than 90% of pts are projected to be alive and progression-free at 5 years post treatment and a negative PET/CT after R-CHT is significantly associated with a longer PFS. Pts with score 4 and 5 had a significantly worse PFS and OS. Hence, the liver uptake may represent a more appropriate cut-point than MBP to identify poor-risk pts who may need early intensification of therapy. The frequent use of IFRT in this study precludes any clear conclusion about its role, but the new IELSG-37 randomized trial will assess whether mediastinal irradiation can be safely omitted in PMLBCL pts achieving a CR after R-CHT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Early Treatment Intensification in Advanced-Stage High-Risk Hodgkin Lymphoma (HL) Patients, with a Positive FDG-PET Scan After Two ABVD Courses – First Interim Analysis of the GITIL/FIL HD0607 Clinical Trial

AbstractAbstract 550 Background:Interim FDG-PET performed after 2 chemotherapy courses (PET-2) is the most powerful predictor of treatment outcome in advanced-stage, ABVD-treated HL (AAHL) patients (pts). Whether early therapy intensification in PET-2 positive HL pts improves overall treatment efficacy for all AAHL pts compared to standard ABVD is still unproven. Patients and study design:In the HD 0607 clinical trial (ClinicalTRial.gov identifier 00795613), AHL (stage IIB-IVB) pts prospectively enrolled by 26 Italian and one Israelian institution are treated with 2 ABVD courses and a PET-2 performed afterwards. PET-2+ pts are randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4+4 courses) or Be+Bb (4+4) and Rituximab (R). PET-2 negative pts are treated with 4 additional ABVD and, upon CR achievement, randomized to either consolidation radiotherapy (Rxt) on the sites of initial bulky disease or no further treatment. Primary endpoint is the efficacy and feasibility of the overall therapeutic strategy. All the non-negative PET-2 (nnPET-2), defined as scans without any residual FDG uptake in any site outside the physiological areas of the tracer concentration, are uploaded in a website for blinded independent central review (BICR) by 6 nuclear medicine experts. Scans are interpreted by visual assessment according to the Deauville 5-point scale (5PS). Results:Starting from 07/2008 till 07/2012, 497 AHL pts were consecutively enrolled and 446 scanned with PET-2. 189/446 (42%) PET-2scans, judged as nnPET-2 by the local PET center, underwent review: 92 were adjudged as positive (62 score 4, 30 score 5) and 97 as negative (score 1–3). Altogether, of 446 pts scanned with a PET-2, 92 (20%) resulted positive and 354 (80%) negative. Age, sex, stage III-IV, bulky, extranodal sites or IPS class where equally distributed among PET-2 positive and negative pts.(p>.05). The median time from PET uploading in the website to review was 45.38 hours, (1–119). The BICR yielded a binary concordance rate among pair of reviewers “very good”, ranging from 0.77 to 0.83 (Cohen’s k coefficient) and a overall concordance rate of 0.77 (Krippendorf’s alpha). In 92 PET-2+ pts, 60 showed a single site of residual uptake in mediastinal (48), laterocervical (4), supraclavear (2), abdominal (3), axillary (1) nodes and in lung (2).In 32 there were ≥ 2 sites of persistent FDG uptake. In 38/40 pts with a positive PET-2 and bulky disease at baseline the residual FDG uptake (singe or multifocal) was seen within the bulky lesion. Overall response to treatment could be assessed in a cohort of 263 pts who had been fully restaged after lymphoma treatment. Forty-one (15%) had a positive and 222 (84%) a negative PET-2 scan. The relative dose intensity (RDI) for Be+Bb ± R and ABVD ± RxT treated pts. was 94.7% and 97.8%, respectively. Among 41 PET-2+ pts CR was achieved in 30 (73%), PR in 1 (2%) Progression or Relapse (Pro/Rel) in 8 (19%) and not evaluable (NE) in 2(5%). Among 222 PET-2- pts. CR was achieved in 212 (95.5%), PR in 2 (1%), Pro/Rel in 6 (3%), NE in 1 (0,5%). Treatment efficacy could be assessed in a cohort of 187 pts. with a complete treatment and a minimum follow-up of 12 months from treatment completion: 27 (15%) with a positive PET-2, treated with Be+Bb ± R and 160 (85%) with a negative PET-2, treated with ABVD ± RxT. The median follow-up from diagnosis was 845 days (101–1345). Among 27 PET-2+ pts, CCR (Continuous CR) was recorded in 22 (81%) Pro/Rel in 5 (18%). Three patients died in CR: 2 for septic shock and one for pneumonia. Among 160 PET-2- pts. CCR was recorded in 146 (91%), Pro/Rel in 9 (5%), Lost of FU (in CR) in 5 (3%). The 1-y PFS was 80.5%, 97.3% and 94.7% for PET-2+, PET-2- p, and for the entire population, respectively. Overall, treatment was well tolerated: 512 Adverse effects were reported: WHO grade 0+1: 453, grade 2: 45. Grade 3 were observed in 12 pts: anemia (2), neutropenia (6), pancytopenia (1), sepsis (1), diverticulitis (1), Vomiting (1). Grade 4 in 2 pts: pneumonia and neutropenia. Conclusions:These preliminary findings suggest that 1) an early switch from ABVD to escalated BEACOPP can be done safely in PET-2 positive pts, with CR achievement in the majority of cases; 2) a centralized online PET scan review system is feasible and allows a real time decision making process, without significant reduction in the RDI administered; 3) 5PS is a reliable interpretation criteria for interim PET scan, with a very good concordance rate among reviewers. Disclosures:No relevant conflicts of interest to declare.

Mutations In the DNA Methyltransferase Gene DNMT3A Are Highly Recurrent In Patients with Intermediate Risk Acute Myeloid Leukemia, and Predict Poor Outcomes

AbstractAbstract 99Whole genome sequencing with next generation technologies represents a new, unbiased approach for discovering somatic variations in cancer genomes. Our group recently reported the DNA sequence and analysis of the genomes of two patients with normal karyotype acute myeloid leukemia (AML). Improvements in next generation sequencing technologies (principally, paired-end sequencing) led us to reevaluate the first case (Ley et al, Nature 456:66–72, 2008) with deeper sequence coverage. We discovered a novel frameshift mutation in DNMT3A, one of the three genes in humans (DNMT1, DNMT3A, and DNMT3B) that encodes a DNA methyltransferase that catalyzes the addition of methyl groups to cytosine within CpG dinucleotides. We then sequenced all the coding exons of this gene in 280 additional de novo cases of AML to define recurring mutations. 62/281 de novo AML cases (22%) had mutations with translational effects in the DNMT3A gene. 18 different missense mutations were identified, the most common of which was at amino acid R882 (37 cases). Frameshifts (n=6), nonsense mutations (n=6), splice site mutations (n=3), and a 1.5 Mbp deletion that included the DNMT3A gene were also identified. DNMT3A mutations were highly enriched in cases with intermediate risk cytogenetics (56/166=33.7%; p<0.0001) and were not found in any cases with favorable cytogenetics (0/79; p<0.0001). Genomic 5-methylcytosine content, the general pattern of CpG island methylation, and gene expression patterns were essentially unaltered in genomes with DNMT3A mutations. The median overall survival of all AML patients with DNMT3A mutations was strikingly reduced, regardless of whether the mutation was at R882 or any other site (12.3 vs. 41.1 months, p<0.0001, Figure A). Patients with a FLT3 ITD mutation and no DNMT3A mutation (n=39) had a median survival of 33.5 months, but patients with a FLT3 ITD mutation and any DNMT3A mutation (n=18) had a median survival of 7.7 months (p=0.003, Figure B). Finally, DNMT3A mutation status independently predicted poor outcomes in a Cox Proportional Hazards analysis. In sum, DNMT3A mutations are highly recurrent in de novo AML cases with intermediate risk cytogenetics, and are independently associated with poor survival. These mutations may be valuable for identifying patients who need early intensification of therapy (allogeneic stem cell transplantation and/or innovative early phase clinical trials in first remission or consolidation). [Display omitted] Disclosures:Westervelt:Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. DiPersio:Genzyme: Honoraria.

Treatment strategies for pediatric acute myeloid leukemia

Therapeutic strategies utilized in recently completed Phase III clinical trials in children with de novo acute myeloid leukemia have led to long-term disease-free survival in 50 – 60% of children. This review describes the contributions from early intensification of therapy and postremission intensification using highly myelosuppressive chemotherapy strategies and discusses the controversial roles of allogeneic bone marrow transplantation, maintenance therapy and CNS irradiation. Current strategies focusing on the identification of critical biologic features and measurements of early response to therapy allow for greatly improved risk group stratification. Future improvements in the treatment of children with acute myeloid leukemia will depend on a better understanding of the biology of the disease, targeted therapeutic approaches directed to specific biologic targets, selective use of allogeneic transplantation and innovative clinical trial designs that will allow for the testing of an increasing number of new agents in increasingly small numbers of patients in defined risk groups.

High-Dose Methotrexate and Early Intensification of Therapy Do Not Improve 3 Year EFS in Children and Adolescents with Disseminated Lymphoblastic Lymphoma. Results of the Randomized Arms of COG A5971

The treatment of pediatric lymphoblastic lymphoma (LL) has developed in parallel with treatment strategies for childhood acute lymphoblastic leukemia using a BFM backbone. The excellent results of the NHL/BFM 90 trial prompted us to design this randomized factorial study to determine whether a regimen without high dose methotrexate (HDMTX) the CCG BFM will result in the same outcome as NHL/BFM-90 and whether intensification with anthracycline and cyclophosphamide would further improve disease free survival.From June 2000 to October 2005, 257 patients with Murphy's Stage III and IV (excluding CNS disease) LL were randomized to one of the four regimens. All regimens used the BFM/NHL95 backbone. The CCG BFM regimen had intrathecal (IT) methotrexate throughout interim maintenance and maintenance without IV methotrexate. The NHL BFM utilized I.V. Methotrexate 5 Gms/m2 and intrathecal MTX every 2 weeks for four doses during interim maintenance without further intrathecal MTX during maintenance. One of each backbone regimens was further intensified with anthracycline and cyclophosphamide early in induction and delayed intensification.The median age was 10.3 years, 195 (76%) were males; 43 (17%) had >5% bone marrow involvement. Twelve patients with CNS disease were not randomized and received intensification and HD HDMTX with delayed CNS radiation (data not reported here).Major toxicities have been related to bone marrow suppression with 4 toxic deaths, 3 due to sepsis and 1 from cerebral hemorrhage. The frequency of grade III/IV neutropenia (alone, with fever or with infection), anemia, and thrombocytopenia were higher in the intensified arms during induction. Three of the four toxic deaths occurred on the intensified arms. The three years EFS of the HDMTX vs. none is 84.5% ± .3.5% vs. 82.7± 3.8 (ρ= 0.93) and the intensification vs. none is 83.4% ±3.7 vs 83.0% ± 3.6 (ρ= 0.66). Therefore, there was no significant difference between treatment arms.These results suggest that neither HDMTX nor early intensification improves EFS in LL. Future direction should focus on identifying biological factors early in therapy so alternative therapies may be investigated.

Use of anti-diabetic drugs and glycaemic control in type 2 diabetes—The Hong Kong Diabetes Registry

In this report, we examined the usage of anti-diabetic treatments including oral anti-diabetic drug (OAD) and/or insulin and their combination from baseline data of a consecutive cohort of 7549 Chinese type 2 diabetic subjects in the Hong Kong Diabetes Registry. Pattern of usage of anti-diabetic treatment and corresponding glycemic control was analyzed. OAD failure was defined as the need to add insulin to maintain glycemic target (glycated hemoglobin, HbA 1c level < 7%) with or without continuation of OAD. There were 4109 [54.4%] women and 3440 [45.6%] men (age: median 57.0 years; range 13–92 years). The mean HbA 1c level was 7.7 ± 1.8% with 39.7% attaining glycemic target. Long disease duration was associated with more complex regimens and the respective rates of OAD failure requiring insulin use were 23.7%, 39.3%, 57.1% and 75.9% in those with disease duration <5 years, 5–9.9 years, 10–19.9 years and ≥20 years ( p < 0.001). In conclusion, in a clinic-based type 2 diabetic population, 39.7% attained glycemic target with HbA 1c < 7%. Long disease duration and complexity of treatment regimens were associated with suboptimal glycemic control. Early intensification of therapy and system improvement are needed to enhance the effectiveness of these drugs in clinical practice.

Management of Early Stage Disease

More than 80% of newly diagnosed patients with chronic myeloid leukemia in chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg imatinib daily. The probability of progression free survival is tightly correlated with the level of response, approaching 100% in those patients who achieve a reduction of BCR-ABL mRNA by at least 3-log at 12 months. High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Standard disease monitoring includes full blood counts, cytogenetics and quantitative RT-PCR for BCR-ABL mRNA but must be tailored to the level of response attained by a given patient. Conservative therapeutic milestones include a complete hematologic response at 3 months, a minor cytogenetic response at 6, a major cytogenetic response at 12 and CCR at 18, but a more aggressive approach may be justified in specific circumstances. Failure to achieve any of these milestones should trigger a re-assessment of the therapeutic strategy. Most patients with CCR remain positive by RT-PCR, and discontinuation of drug is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells. The mechanisms underlying disease persistence are not well understood. Evidence is accumulating that early therapy intensification using high doses of imatinib (800 mg daily) or imatinib in combination with cytarabine or interferon-alpha may induce higher rates of RT-PCR negativity. Large studies will be required to determine whether this translates into improved progression free and overall survival.