Integration of Publicly Reported Center Outcomes into Standards and Accreditation: The FACT Model.

The rapid evolution of blood and marrow transplantation (BMT), coupled with diverse outcomes associated with heterogeneous groups of patients, led to the formation of 2 important organizations early in the development of the field: the Center for International Blood and Marrow Transplant Research (CIBMTR) and the Foundation for the Accreditation of Cellular Therapy (FACT). These organizations have addressed 2 of the 9 elements identified by the National Quality Strategy (NQS) for achieving better health care, more affordable care, and healthy people and communities: a registry that promotes improvement of care and accreditation based on quality standards. More recently, a federally mandated database in the United States addresses the third element of the NQS: public reporting of treatment results. Here we describe the current process by which FACT incorporates patient outcomes reported by the CIBMTR into standards for accreditation, the requirements for accredited programs with performance below expected outcomes to maintain accreditation, and preliminary findings of an assessment of corrective action plans intended to improve outcomes.

Effect of Aging and Predonation Comorbidities on the Related Peripheral Blood Stem Cell Donor Experience: Report from the Related Donor Safety Study.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 109/L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals.

Related peripheral blood stem cell donors experience more severe symptoms and less complete recovery at one year compared to unrelated donors.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P<0.001] and severe (OR 8.91; P<0.001) pain and toxicities (OR 1.84; P<0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P=0.021) and non-recovery from pain (OR 1.42; P=0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P<0.001) and non-recovery from toxicities (OR 3.71; P<0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation (P=0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636.

Donor Lymphocyte Infusions Used to Treat Mixed-Chimeric and High-Risk Patient Populations in the Relapsed and Nonrelapsed Settings after Allogeneic Transplantation for Hematologic Malignancies Are Associated with High Five-Year Survival if Persistent Full Donor Chimerism Is Obtained or Maintained.

Mixed chimerism (MC), a persistent or increasing number of host cells after allogeneic hematopoietic stem cell transplantation (HSCT), is a predictor of disease relapse. Donor lymphocyte infusions (DLI) have the potential to enhance the graft-versus-malignancy (GVM) effect, reducing the risk of relapse in patients with MC. Hence, in addition to utilizing DLI in the relapsed setting, there is a motivation to pursue pre-emptive DLI for patients in complete remissions after HSCT. To assess the safety and efficacy of DLI, records of 86 patients who received DLI between 2003 and 2015 at a single institution were studied retrospectively. Patients who received DLI included 50 patients with relapsed/residual (RR) disease, 29 patients with emerging MC without detectable disease, and 7 patients in an "other" cohort who had neither RR disease nor emerging MC after HSCT. DLI were administered using a dose-escalation protocol. After DLI, 93% of MC patients converted to full donor chimerism (FDC). Nonrelapsed patients (MC and other) reported high overall survival (OS) at 1 and 5 years (83% at 1 year, 70% at 5 years for MC; 86% at 1 year, 69% at 5 years for other) and was statistically superior to 5-year OS for RR patients (nonrelapsed 69% versus RR 28%; P = .00032). Improved survival correlated with successful conversion to FDC after DLI for RR and MC cohorts: 71% 2-year OS for patients converted to FDC versus 13% for patients who failed to achieve FDC (P < .0001). DLI for nonrelapsed patients was associated with a superior 5-year progression-free survival (PFS) of 71% compared with 18% 5-year PFS in the RR group (P < .0001). Relapse/progressive disease was the most frequent cause of death (41%). Seven MC (24%), 2 other (29%), and 39 RR patients (78%) relapsed or did not respond after DLI. Overall, 6 patients (7%) died of graft-versus-host disease after DLI. Our results demonstrate a successful dose-escalation approach for nonrelapsed patients that correlated with high survival and a high rate of achieving FDC in MC and RR populations. DLI remain a viable option to boost the GVM effect in the relapsed setting and may pre-emptively protect against relapse in MC populations after HSCT.

Impact of Public Reporting of Center-Specific Survival Analysis Scores on Patient Volumes at Hematopoietic Cell Transplant Centers.

The Center for International Blood and Marrow Transplant Research reports the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) at United States transplantation centers (TC) annually through its Center-Specific Survival Analysis (CSA). The CSA compares the actual 1-year overall survival (OS) and predicted 1-year OS rate after alloHCT at each TC, which is then reported as 0 (OS as expected), -1 (OS worse than expected), or 1 (OS better than expected). We evaluated the impact of public reporting of TC performance on their alloHCT patient volumes. Ninety-one TCs that serve adult or combined adult and pediatric populations and had CSA scores reported for 2012-2018 were included. We analyzed prior-calendar-year TC volume, prior-calendar-year CSA score, whether the CSA score had changed in the prior year from two years earlier, calendar year, TC type (adult only vs. combined adult and pediatric), and years of alloHCT experience for their impact on patient volumes. A CSA score of -1, as compared with 0 or 1, was associated with an 8% to 9% reduction in the mean TC volume (P < 0.001) in the subsequent year, adjusting for the prior year center volume. Additionally, being a TC neighboring an index TC with a -1 CSA score, was associated with a 3.5% increase in mean TC volume (P = 0.04). Our data show that public reporting of CSA scores is associated with changes in alloHCT volumes at TCs. Additional investigation into the causes of this shift in patient volume and the impact on outcomes is ongoing.

Clinical roundtable monograph: Unmet needs in the management of chronic myelogenous leukemia.

Approximately 5,000 cases of chronic myelogenous leukemia (CML) are diagnosed each year in the United States. The introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved survival time for many CML patients. Current first-line treatment options include imatinib and the second-generation agents nilotinib and dasatinib. Second- and third-line agents include nilotinib, dasatinib, bosutinib, and the new agent ponatinib. Despite the effectiveness of TKIs, some patients develop resistance or intolerance to these agents. A number of mutations of the BCR-ABL gene have been identified and are associated with TKI resistance. Patients may benefit from switching to a second-line TKI, undergoing hematopoietic stem cell transplant, or receiving newly emerging agents. Although early response is associated with improved patient outcome, clinicians lack tests that can determine which patients will benefit from which therapies. To ensure adequate response, patients should be monitored by both polymerase chain reaction and cytogenetic analysis of the bone marrow. This roundtable monograph reviews key unmet needs in patients with CML related to disease management and treatment options.

Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia.

PURPOSE: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS: One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS: Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION: Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Transportation of peripheral blood progenitor cell products: effect of ambient temperature.

BACKGROUND AIMS: Peripheral blood progenitor cell (PBPC) products are often transported at high cell concentrations (>200 × 109/L) over long distances, requiring >36 h transport time. METHODS: Fresh PBPC samples from eight healthy donors were studied with two viability assays for effects of temperature outside the transport container (ambient temperature). The Coleman 5272 container, routinely used by the National Marrow Donor Program (NMDP) with two -20°C gel packs, was compared with the Coleman 6216 container, which can hold four -20°C gel packs. RESULTS: The temperature inside the smaller transport container (5272) proved to be sensitive to ambient temperature, whereas the larger container (6216) was less sensitive. The viability of CD34(+) cells, and the survival of granulocyte-macrophage colony-forming units (GM-CFU), was more dependent on the ambient temperature for the smaller than for the larger container. CONCLUSIONS: PBPC products are most often transported at approximately 2-8°C. The inside temperature of the container currently used by the NMDP appears to be more sensitive to increases in temperature when exposed to higher ambient temperature for prolonged periods of time. Increasing the number of gel packs from two to four improves the stability of the temperature inside the container but would require a different container.

Transportation of peripheral blood progenitor cell products: effects of time, temperature and cell concentration.

BACKGROUND AIMS: Peripheral blood progenitor cell (PBPC) products are often transported at high cell concentrations (>200x10(9)/L) over long distances, requiring >36 h transport time. METHODS: Fresh PBPC samples from 12 healthy donors were studied with various viability assays regarding the effects of temperature, cell concentration and duration of storage. RESULTS: Trypan blue exclusion was far less sensitive to cell damage than two-color fluorescence for CD34 and 7-AAD, and colony-forming unit-granulocyte-macrophage (CFU-GM) assays; the latter assay proved the most sensitive. All products stored at 4 degrees C maintained their viability for up to 4 days. Thus, at 96 h, recovery of viable CD34(+) cells was still 82%, and of CFU-GM 57%, even at concentrations of 200x10(9)/L. Higher storage temperatures rapidly decreased the viability, with extensive variation between donors. At room temperature 80% of viable CD34(+) cells and >90% of CFU-GM were lost after 48 h of storage at 200x10(9)/L. Lower cell concentrations allowed storage at higher temperatures: at 17 degrees C a concentration of 50x10(9)/L resulted in only 5% loss of viable CD34(+) cells after 48 h, while the loss was >30% at 200x10(9)/L. CONCLUSIONS: PBPC products should be transported at 4 degrees C. Dilution of the product may partly compensate for slightly higher temperatures. Trypan blue exclusion should be abandoned as a method for assessing viability after prolonged transportation. Proliferative assays should be used to validate transportation conditions.

Starting granulocyte-colony-stimulating factor (filgrastim) early after autologous peripheral blood progenitor cell transplantation leads to faster engraftment without increased resource utilization.

BACKGROUND: Hematopoietic growth factor support is routinely used after autologous stem cell transplantation. The optimal starting date of this growth factor support has not been established yet, but many engraftment studies now recommend the fifth day after stem cell infusion (Day 5). STUDY DESIGN AND METHODS: After switching the start date of granulocyte-colony-stimulating factor (G-CSF) support from the day of transplant (Day 0 group), to Day 5 after stem cell infusion (Day 5 group), the impression arose that there was an associated delay in engraftment of both white blood cells and platelets (PLTs). A retrospective analysis of two cohorts was performed with attention to engraftment variables and resource utilization. RESULTS: Patients in the Day 0 group recovered an absolute granulocyte count of more than 0.500 x 10(9) per L significantly earlier than patients in the Day 5 group (p < 0.001 in log-rank test; median difference, 1 day). Time to PLT recovery of more than 20 x 10(9) per L, without transfusion support, was not significantly different between the Day 0 and Day 5 groups (p = 0.16; medians of 10 and 12 days, respectively). Resource utilization, defined as number of red blood cell and PLT transfusions, days with fever or on intravenous antibiotics, days with mucositis, and length of hospital stay, were not significantly different between the two groups (p >or= 0.15 in each case). Total charges for the transplant episode were also not different between the two groups (p = 0.48). CONCLUSION: Starting G-CSF support on the day of stem cell infusion, instead of on Day +5, leads to faster hematologic recovery without a significant impact on resource utilization.

Effects of extensive splenomegaly in patients with myelofibrosis undergoing a reduced intensity allogeneic stem cell transplantation.

Changes in spleen size postallogeneic haematopoietic stem cell transplantation (HSCT) in patients with primary myelofibrosis have been poorly characterized. We analysed 10 patients with myelofibrosis and splenomegaly following a reduced-intensity allogeneic HSCT. All patients fully engrafted donor cells including five patients with extensive splenomegaly. Extensive splenomegaly was associated with a prolonged time to neutrophil and platelet recovery. In all 10 patients, a progressive reduction of splenomegaly was documented within 12 months post-transplant and paralleled the reduction of marrow fibrosis. These findings suggest that myelofibrosis patients with extensive splenomegaly may proceed with allogeneic HSCT without prior splenectomy.

Improving Outcomes in Chronic Myeloid Leukemia Over Time in the Era of Tyrosine Kinase Inhibitors.

Most patients with chronic myeloid leukemia (CML) receiving treatment with BCR-ABL1 tyrosine kinase inhibitors (TKIs) will achieve favorable responses. Moreover, TKI therapy enables patients to experience long-term survival, with survival rates similar to those of individuals without CML. This enhanced survival has resulted from the availability of multiple BCR-ABL1 TKIs with efficacy, not only in frontline treatment, but, importantly, also in second- and third-line treatment. We have reviewed the changes in long-term outcomes in the era of TKI therapy and how these changes have affected treatment practices. We discuss the development of imatinib, the first BCR-ABL1 TKI, followed by newer TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib. We consider the key studies that led to their development as frontline or later-line therapies, their safety profiles, and their effect on improving patient outcomes. With these improved outcomes, the definition of an optimal response has become more stringent, and treatment monitoring strategies have changed. Second-line patient populations have evolved from those with resistance to, or intolerance of, imatinib to those with moderate responses to, or low-grade adverse events with, imatinib. Although all TKIs are associated with high survival rates, newer TKIs have been associated with lower disease progression rates and, importantly, deeper treatment responses and, potentially, a greater chance of future treatment-free remission. Finally, we consider the unmet needs of patients with CML, including the challenges remaining for those without optimal responses during TKI therapy and new therapies and strategies to identify such patients at diagnosis.

Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib.

BACKGROUND: The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. METHODS: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy (N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. RESULTS: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. CONCLUSIONS: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

Considering baseline factors and early response rates to optimize therapy for chronic myeloid leukemia in chronic phase.

Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are available for the treatment of chronic myeloid leukemia in chronic phase (CML-CP), and several baseline and on-treatment predictive factors have been identified that can be used to help guide TKI selection for individual patients. In particular, early molecular response (EMR; BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. Here we review data supporting the importance of achieving EMR for improving patients' long-term outcomes and discuss key considerations for selecting a frontline TKI in light of these data. Because a higher proportion of patients achieve EMR with second-generation TKIs such as nilotinib and dasatinib than with imatinib, these TKIs may be preferable for many patients, particularly those with known negative prognostic factors at baseline. We also discuss other considerations for frontline TKI choice, including toxicities, cost-effectiveness, and the emerging goals of deep molecular response and treatment-free remission.

Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia.

With BCR-ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, many patients with chronic myeloid leukemia in chronic phase (CML-CP) can expect to live near-normal life spans. Current treatment recommendations of the National Comprehensive Cancer Network and the European LeukemiaNet state that patients with CML-CP should remain on TKI therapy indefinitely. However, there is increasing evidence from clinical trials that some patients with sustained deep molecular responses may be able to achieve treatment-free remission (TFR), whereby they can suspend TKI therapy without losing previously achieved responses. With many patients achieving deep molecular responses to TKI therapy, there is growing interest in whether such patients can achieve TFR. In addition, adverse events (AEs) with long-term TKI therapy, including both the potential for later-emerging AEs and chronic, low-grade AEs, represent a major motivator for oncologists and their patients to investigate the feasibility of TFR. In this review, we provide an overview of data from TFR clinical trials, discuss the importance of achieving a deep molecular response to TKI treatment, and consider potential reasons for investigating TFR following TKI therapy.

Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study.

BACKGROUND: Many patients with chronic myeloid leukemia in chronic phase experience chronic treatment-related adverse events (AEs) during imatinib therapy. These AEs can impair quality of life and lead to reduced treatment adherence, which is associated with poor clinical outcomes. PATIENTS AND METHODS: In the phase II ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study (N = 52), the effect of switching patients with imatinib-related chronic low-grade nonhematologic AEs from imatinib to nilotinib was evaluated. RESULTS: Three months after switching to nilotinib, 84.6% of the patients had overall improvement in imatinib-related AEs (primary endpoint). Of 210 imatinib-related AEs identified at baseline, 62.9% had resolved within 3 months of switching to nilotinib. Of evaluable patients, most had improvements in overall quality of life after switching to nilotinib. At screening, 65.4% of evaluable patients had a major molecular response (BCR-ABL1 ≤ 0.1% on the International Scale). After switching to nilotinib, the rate of the major molecular response was 76.1% at 3 months and 87.8% at 12 months. Treatment-emergent AEs reported with nilotinib were typically grade 1 or 2; however, some patients developed more serious AEs, and 8 patients discontinued nilotinib because of new or worsening AEs. CONCLUSION: Overall, results from the ENRICH study demonstrated that switching to nilotinib can mitigate imatinib-related chronic low-grade nonhematologic AEs in patients with chronic myeloid leukemia in chronic phase, in conjunction with acceptable safety and achievement of molecular responses. This trial was registered at www.clinicaltrials.gov as NCT00980018.

Barriers to physician adherence to evidence-based monitoring guidelines in chronic myelogenous leukemia.

PURPOSE: Although monitoring of cytogenetic/molecular responses to therapy in chronic myelogenous leukemia (CML) facilitates superior outcomes, less than one half of CML patients are monitored using published evidence-based guidelines. Barriers to physician adherence with guidelines are unknown. METHODS: An anonymous survey was mailed to 515 hematologist-oncologists in New Jersey and Indiana exploring attitudes toward monitoring guidelines. RESULTS: Ninety-six physicians (19%) responded-89% in community practice, 83% with more than 10 years of experience, and 92% caring for CML patients. Eighty-four percent self-reported using CML monitoring guidelines, 14% were familiar with but did not adopt guidelines and 2% were unfamiliar. Eighty-four percent performed molecular monitoring quarterly as recommended; 6% did not perform molecular monitoring at all during the first year. Guidelines were considered evidence based by 98%, but only 54% strongly considered them easy to find; only 51% strongly felt they addressed all aspects of disease management. Patient resource barriers were a significant deterrent toward implementation with 30% citing high costs. Physician resources, including lack of time to search guidelines, limited use in one fifth. Despite 90% believing an online database helpful, between one third and one half did not feel that additional training, professional society endorsements, or availability of expert consultations would encourage use. CONCLUSIONS: Significant barriers to adherence with evidence-based CML guidelines exist. Resource barriers, lack of familiarity and lack of agreement restrict adoption, but efforts to facilitate use are not desired. Multifaceted educational strategies, including automated computerized reminders at point of care, are needed to improve quality outcomes in CML.

Correlations between cytogenetic and molecular monitoring among patients with newly diagnosed chronic myeloid leukemia in chronic phase: post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study.

CONTEXT: Although bone marrow (BM) karyotyping has been the standard in monitoring patients with chronic myeloid leukemia, peripheral blood (PB) monitoring methods may be more convenient. OBJECTIVE: To conduct post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study to evaluate correlations between results of cytogenetic testing and molecular monitoring from BM and PB during the first 18 months of high-dose imatinib therapy, and between early and late molecular responses. DESIGN: Newly diagnosed patients with chronic-phase chronic myeloid leukemia received imatinib 400 mg twice daily and were monitored quarterly for up to 18 months. Cytogenetic testing was performed by karyotyping using BM or by fluorescence in situ hybridization using PB. Molecular testing was performed by quantitative reverse transcriptase polymerase chain reaction using BM and PB. RESULTS: Significant pairwise correlations were found between results obtained by karyotyping, fluorescence in situ hybridization, and quantitative reverse transcriptase polymerase chain reaction using PB or BM (all pairwise correlations >0.8; P < .001). At 12 months, cytogenetic response by karyotyping correlated well with response by fluorescence in situ hybridization. A median 2.579-log reduction in BCR-ABL1 level from a standardized baseline correlated with fluorescence in situ hybridization-negative status. Patients with greater than 2-log reduction in BCR-ABL1 level at 3, 6, and 9 months were more likely to achieve major molecular response at 18 months than those with 2-log reduction or less. CONCLUSIONS: Our findings support the feasibility of molecular monitoring using PB and suggest that molecular monitoring conducted at a single reliable reference laboratory can adequately track response without invasive BM testing. Our findings are consistent with other work indicating that early response to imatinib predicts favorable long-term outcome.

Translating trial-based molecular monitoring into clinical practice: importance of international standards and practical considerations for community practitioners.

The success of tyrosine kinase inhibition of the BCR-ABL fusion gene with imatinib in the treatment of chronic myeloid leukemia (CML) has resulted in the use of molecular detection techniques for routine clinical management. Current clinical guidelines recommend the use of molecular testing of BCR-ABL transcript levels by quantitative real-time transcriptase polymerase chain reaction (qRT-PCR) every 3 to 6 months. However, qRT-PCR methods have not yet been standardized, particularly in the United States, where most patients are initially treated outside of academic practices. The lack of standard methods for molecular monitoring has resulted in the failure to follow National Comprehensive Cancer Network and European LeukemiaNet guideline recommendations and in the misinterpretation of test results. Standardization of molecular monitoring methods and adherence to guideline recommendations are important for optimal patient management. In this article, we provide an update on the current clinical trial results by using the molecular technique to monitor patient response. Current problems and efforts in standardizing the qRT-PCR technique and reporting are reviewed. We provide examples of potential problems of various reference laboratory reports and present recommendations for assessing molecular test results. These recommendations seem particularly important because nilotinib and dasatinib appear to have improved the molecular response in the initial treatment of CML.