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Purpose To provide evidence-based guidance on the use of platelet transfusion in people with cancer. This guideline updates and replaces the previous ASCO platelet transfusion guideline published initially in 2001. Methods ASCO convened an Expert Panel and conducted a systematic review of the medical literature published from September 1, 2014, through October 26, 2016. This review builds on two 2015 systematic reviews that were conducted by the AABB and the International Collaboration for Transfusion Medicine Guidelines. For clinical questions that were not addressed by the AABB and the International Collaboration for Transfusion Medicine Guidelines (the use of leukoreduction and platelet transfusion in solid tumors or chronic, stable severe thrombocytopenia) or that were addressed partially (invasive procedures), the ASCO search extended back to January 2000. Results The updated ASCO review included 24 more recent publications: three clinical practice guidelines, eight systematic reviews, and 13 observational studies. Recommendations The most substantial change to a previous recommendation involved platelet transfusion in the setting of hematopoietic stem-cell transplantation. Based on data from randomized controlled trials, adult patients who undergo autologous stem-cell transplantation at experienced centers may receive a platelet transfusion at the first sign of bleeding, rather than prophylactically. Prophylactic platelet transfusion at defined platelet count thresholds is still recommended for pediatric patients undergoing autologous stem-cell transplantation and for adult and pediatric patients undergoing allogeneic stem-cell transplantation. Other recommendations address platelet transfusion in patients with hematologic malignancies or solid tumors or in those who undergo invasive procedures. Guidance is also provided regarding the production of platelet products, prevention of Rh alloimmunization, and management of refractoriness to platelet transfusion ( www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki ).

Purpose: The ASCO Value Framework calculates the value of cancer therapies. Given costly novel therapeutics for chronic lymphocytic leukemia, we used the framework to compare net health benefit (NHB) and cost within Medicare of all regimens listed in the National Comprehensive Cancer Network (NCCN) guidelines. Methods: The current NCCN guidelines for chronic lymphocytic leukemia were reviewed. All referenced studies were screened, and only randomized controlled prospective trials were included. The revised ASCO Value Framework was used to calculate NHB. Medicare drug pricing was used to calculate the cost of therapies. Results: Forty-nine studies were screened. The following observations were made: only 10 studies (20%) could be evaluated; when comparing regimens studied against the same control arm, ranking NHB scores were comparable to their preference in guidelines; NHB scores varied depending on which variables were used, and there were no clinically validated thresholds for low or high values; treatment-related deaths were not weighted in the toxicity scores; and six of the 10 studies used less potent control arms, ranked as the least-preferred NCCN-recommended regimens. Conclusion: The ASCO Value Framework is an important initial step to quantify value of therapies. Essential limitations include the lack of clinically relevant validated thresholds for NHB scores and lack of incorporation of grade 5 toxicities/treatment-related mortality into its methodology. To optimize its application for clinical practice, we urge investigators/sponsors to incorporate and report the required variables to calculate the NHB of regimens and encourage trials with stronger comparator arms to properly quantify the relative value of therapies.

7000 Background: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. Methods: Pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg →15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee. Results: 283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/29%. Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤ 1% BCR-ABL1IS; 30 mg→15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations. Clinical trial information: NCT02467270. [Table: see text]

e18889Background: Prior studies have shown that subsidies for low-income patients (LIS pts) improve TKI initiation. Prices increased after 2010 when more TKIs for frontline treatment were approved....

Purpose Because both t(8;21) and inv(16) disrupt core binding factor (CBF) in acute myeloid leukemia (AML) and confer relatively favorable prognoses, these cytogenetic groups are often treated similarly. Recent studies, however, have shown different gene profiling for the two groups, underscoring potential biologic differences. Therefore, we sought to determine whether these two cytogenetic groups should also be considered separate entities from a clinical standpoint. Patients and Methods We analyzed 144 consecutive adults with t(8;21) and 168 with inv(16) treated on Cancer and Leukemia Group B front-line studies. We compared pretreatment features, probability of achieving complete remission (CR), overall survival (OS) and cumulative incidence of relapse (CIR) between the two groups. Results With a median follow-up of 6.4 years, for CBF AML as a whole, the CR rate was 88%, 5-year OS was 50% and CIR was 53%. After adjusting for covariates, patients with t(8;21) had shorter OS (hazard ratio [HR] = 1.5; P = .045) and survival after first relapse (HR = 1.7; P = .009) than patients with inv(16). Unexpectedly, race was an important predictor for t(8;21) AML, in that nonwhites failed induction more often (odds ratio = 5.7; P = .006) and had shorter OS than whites when certain secondary cytogenetic abnormalities were present. In patients with t(8;21) younger than 60 years, type of induction also correlated with relapse risk. For inv(16) AML, secondary cytogenetic abnormalities (especially +22) and male sex predicted better outcome. Conclusion When the prognostic impact of race, secondary cytogenetic abnormalities, sex, and response to salvage treatment is considered, t(8;21) and inv(16) AMLs seem to be distinct clinical entities and should be stratified and reported separately.

Therapy for younger patients with acute myeloid leukemia (AML) is administered with curative intent. After complete remission (CR) is achieved with initial induction therapy, some form of postremission therapy is required to prevent relapse, and the choice is generally between a few courses of high-dose cytarabinebased chemotherapy or one to two courses of chemotherapy followed by allogeneic stem-cell transplantation. The latter comes in a variety of different flavors, most often using fully human leukocyte antigen (HLA) –matched sibling donors, but now with an expanding choice of unrelated, cord blood, or haploidentical donors as well as a range of myeloablative or reduced-intensity pretransplantation conditioning regimens. Randomized trials have failed to show an advantage of autologous transplantation (perhaps because so many of the marrows were contaminated by minimal residual disease that was not detectable with the technology available at that time), and there is no benefit from continued maintenance chemotherapy. It has been difficult to prove that allogeneic transplantation is superior to chemotherapy alone when applied to the broad, biologically heterogeneous population of younger patients with AML. The trials that have been performed are somewhat imperfect in that patients were assigned to transplantation if they had an HLA-matched sibling, rather than being strictly randomly assigned. In addition, many patients declined transplantation, leading to the imaginative so-called donor versus no donor comparisons that were intended to mimic intent-to-treat analyses. A recent meta-analysis of these randomized trials has suggested that allogeneic transplantation in first CR provides the greatest advantage for patients in higher risk groups as defined by cytogenetics and somewhat less benefit for the markedly heterogeneous groups of patients who are characterized as intermediate risk. The relapse rate is lower after allogeneic transplantation because the graft versus leukemia effect makes an important contribution to the overall outcome. This is balanced by higher rates of treatment-related mortality and morbidity, although there have been improvements in transplantation techniques and considerably reduced short-term mortality in recent years. And indeed, even as a card-carrying member of the nontransplanters union, I acknowledge and so inform my patients that the survival after transplantation has never been shown to be worse than with chemotherapy consolidation in the comparative trials. When counseling patients in first remission, most clinicians also mention that the initial decision is only the first part of the calculation, given that patients who relapse can subsequently receive a transplant in second remission. That said, until now, this could only be stated in a general way because there have been virtually no systematic data that address the feasibility and outcome of later transplantation. Problems include the difficulties in achieving a second remission, the development of complications during reinduction that could preclude transplantation, the administrative delays imposed by insurers, delays in identifying unrelated donors if siblings are not available, and an appreciable post-transplantation relapse rate, among others. Hence the importance of the large and unique analysis from the Medical Research Council (MRC) of the United Kingdom that accompanies this editorial. This is a real-world experience in that the MRC enrolls an extraordinarily high fraction of United Kingdom patients with newly diagnosed AML onto clinical trials and has good follow-up of these individuals. The authors focus on 1,271 patients in first relapse, age 16 to 50 years, who had not received an allogeneic transplant in first CR; 19% of these relapsed patients were alive at 5 years after relapse with a major effect of cytogenetic risk category (32% for favorable, 17% for intermediate, and only 7% for high risk). Other salient findings included the following. First, a perhaps higher than expected rate of second CR was achieved in 55% of patients, and the 5-year overall survival of these responders was 34%. The CR rate varied according to risk group and, although it is not stated explicitly, it is likely that the probability of second CR was strongly affected by the duration of first CR. Second, remarkably, 67% of the remitters could receive transplantations in second CR (perhaps because many of these patients had donors who were identified in first CR but chose not to undergo transplantation, and because they were being observed as part of a clinical trial) with a 5-year survival of 44% in those undergoing one of many different types of allogeneic transplantation. It remains to be seen whether such a high fraction of patients could receive transplantations in the United States, but emphasizes the importance of beginning donor searches at the time of diagnosis. Third, chemotherapy alone could have served as salvage treatment for 16% of those achieving second CR who did not undergo JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 10 APRIL 1 2013

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin’s lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication. PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML. RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P = .007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months). CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.

PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. PATIENTS AND METHODS: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m2/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. RESULTS: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P < .001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P = .007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P = .001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P = .03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. CONCLUSION: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.

e18547 Background: TKIs have revolutionized outcomes for CML patients (pts) but are not without cost or side effects. For pts with a prolonged response to treatment, discontinuing (d/c) treatment is appealing and has been investigated in a number of trials. In pts in whom treatment was stopped, musculoskeletal (MSK) symptoms were reported that were shown in some cases to resolve with resuming TKIs. Methods: Records of pts with chronic phase CML who stopped TKIs were reviewed. Results: We report 8 pts with chronic phase CML whose TKI was stopped following a prolonged molecular remission. 5 pts were receiving imatinib and 3 dasatinib. 5 pts were experiencing intolerable side effects of TKIs and agreed to a trial of d/c; 2 pts requested d/c; a third pt was planning for pregnancy. The median duration of therapy with TKI before d/c was 10 years. 6/8 pts developed MSK complaints with arthralgias and joint stiffness after cessation. Involved joints included the cervical spine, shoulders, elbows, small joints of the hand, hips and knees. Arthralgia was Grade 1 in 3 pts, and Grades 2 and 3 in 1 and 2 pts, respectively. Joints were not swollen, erythematous or tender to touch. The median time from cessation of TKIs to the onset of symptoms was 2.25 mos (range: < 1-6 months). 3 pts with symptoms underwent rheumatologic work up that was nonrevealing. 5/8 pts remain in molecular remission. Of the 3 with molecular relapse, 2 had arthralgias that improved with resuming TKIs; the third remained asymptomatic. Of those who did not relapse, 1 remains symptom-free and 2 had resolution of their MSK symptoms. 1 had little benefit with corticosteroid therapy and imatinib was resumed. However, this retreatment was d/c due to side effects and she continues to experience mild arthralgias. 1 pt did not benefit from resuming TKIs, which was therefore d/c. Conclusions: The etiology of the so-called TKI “withdrawal syndrome” remains unclear. The incidence of this syndrome has not been fully elucidated, and it seems to be underappreciated and perhaps under-reported by patients. Although most symptoms are relatively mild and self-limited, this should be discussed with patients considering stopping TKIs.

Objective: To determine the most effective, evi- dence-based approach to the use of platelet transfu- sions in patients with cancer. Outcomes: Outcomes of interest included prevention of morbidity and mortality from hemorrhage, effects on survival, quality of life, toxicity reduction, and cost-effectiveness. Evidence: A complete MedLine search was per- formed of the past 20 years of the medical literature. Keywords included platelet transfusion, alloimmuniza- tion, hemorrhage, threshold and thrombocytopenia. The search was broadened by articles from the bibliog- raphies of selected articles. Values: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly related to one of the primary outcomes in a randomized design. Benefits/Harms/Cost: The possible consequences of different approaches to the use of platelet transfusion were considered in evaluating a preference for one or another technique producing similar outcomes. Cost alone was not a determining factor. Recommendations: Appendix A summarizes the rec- ommendations concerning the choice of particular platelet preparations, the use of prophylactic platelet transfusions, indications for transfusion in selected clin- ical situations, and the diagnosis, prevention, and man- agement of refractoriness to platelet transfusion. Validation: Five outside reviewers, the ASCO Health Services Research Committee, and the ASCO Board re- viewed this document. Sponsor: American Society of Clinical Oncology J Clin Oncol 19:1519-1538. © 2001 by American Society of Clinical Oncology. INTENSIVE THERAPIES producing severe and sus- tained thrombocytopenia are used routinely in patients with hematologic malignancies and are being applied to many patients with solid tumors as well. Advances in platelet collection, storage, and transfusion have decreased the morbidity of such therapies, and death from hemorrhage is now an unusual occurrence, despite the larger number of patients being treated aggressively. Platelet transfusions are expensive, however, and are associated with a number of side effects including febrile or allergic transfusion reac- tions, transmission of bacterial and viral infections, circu- latory congestion, transfusion-related acute lung injury and alloimmunization. The ASCO Health Services Research Committee elected to convene an Expert Panel to design guidelines for platelet transfusion because of perceived wide variation in platelet transfusion practices. This paper will first describe the types of platelet products available for transfusion and then provide evidence-based guidelines for use in different clinical situations.

TPS7103 Background: Myelodysplastic syndrome (MDS) is a group of clonal bone marrow disorders associated with an increased risk of transformation to acute myeloid leukemia (AML). Despite recent pro...

Major advances in understanding the biology of hematologic malignancies and the development of new therapies are occurring at a rapid pace, and Journal of Clinical Oncology (JCO) is committed to offering the oncology community and oncology experts the most up-to-date information pertinent to our research and practice. In this context, it became clear that an issue of JCO dedicated to updating the pathophysiology, molecular pathogenesis, and therapies of leukemias and myelodysplastic syndrome (MDS) would be valuable.

6506 Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as 1st- and 2nd-line therapy for CML pts with newly diagnosed disease or resistance/intolerance to imatinib. This ongoing study in pts with imatinib-resistant/-intolerant CML provides the longest follow-up of a second-generation BCR-ABL inhibitor. Methods: Study design has been described (Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML (N=670) were randomized to dasatinib 100 mg once daily (QD), 50 mg twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151 pts (74%) remain on QD dosing, 85 of whom (56%) are on ≥100 mg QD dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%) originally randomized to BID dosing having switched to QD dosing. For pts randomized to the 100 mg QD arm (n=167), progression-free survival (PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate of transformation to advanced disease. In exploratory analyses, 42% and 60% of pts had BCR-ABL levels ≤10% (International Scale) at 1 and 3 months (mos), respectively. In a landmark analysis, BCR-ABL ≤10% at 1 or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD, nonhematologic adverse events (AEs; all grades) generally first occurred in

6512 Background: Dasatinib, a potent tyrosine kinase inhibitor, is indicated for treating imatinib-resistant or -intolerant patients with CML (all phases) or Ph+ acute lymphoblastic leukemia. Based...

6569 Background: Management of chronic myeloid leukemia (CML) has evolved from nonspecific conventional chemotherapy with hydroxyurea or busulfan, with poor efficacy, to therapy with interferon-α a...

6553 Background: Persistent clonal expansion of cytotoxic T or NK cells has been described in patients with CML and Ph+ ALL during dasatinib therapy. Methods: Data from phase II and III trials of d...

6518 Background: This exploratory analysis examined potential relationships between dasatinib exposure and the long-term safety and efficacy outcomes of subjects enrolled in CA180-034, a phase III dose-optimization study in CML-CP patients with 4-arms (100 mg QD, 50 mg BID, 140 mg QD, and 70 mg BID). The following endpoints at 2-year follow-up were examined: (a) long-term outcomes [progression free-survival (PFS) and overall survival (OS)], (b) durability of complete cytogenetic response (CCyR), and (c) development of Gr 3/4 nonhematologic adverse events (AEs). Methods: Exposure-response (E-R) analysis was performed with summary steady-state measures of dasatinib exposure determined previously from a population pharmacokinetic (PPK) model (peak [Cmax], trough [Cmin], and time-averaged [Cavg] plasma concentration) in 567 subjects enrolled in CA180-034, for whom exposure data were available (Wang et al, ASCO 2008). E-R analysis of PFS, OS, and durability of CCyR were examined by Kaplan-Meier (K-M) analysis ...

18535 Background: Malfunction of CVAPs is common in cancer patients receiving chemotherapy. We evaluated the role of venography as a means of assessing the cause of malfunction. Methods: We reviewed and analyzed data available from cancer patients who had a venogram for a malfunctioning CVAP between 1/03 to 3/05. All patients in our institution who have a malfunctioning CVAP receive a trial of intracatheter thrombolytics. If the malfunction persists, then a venogram is performed through the catheter. Results: Seventy-seven patients were studied. The indication for evaluation was inability to aspirate blood (54%), pain (18%), swelling at site of injection (10%), difficult aspiration and infusion (6.5%) and others (11.5%). Forty-four patients had chest ports (31% left and 26% right side), while 33 patients had the CVAP placed in the upper extremity (24% right and 18% left arm). Fibrin sheath or thrombus was the most common finding in 44% of patients, and 41% of venograms were normal. Only two patients had soft tissue extravasation of contrast. Sites of extravasation were in the chest at the catheter/port junction and in the supraclavicular area secondary to a catheter fracture. In patients with aspiration failure, 68% had either a fibrin sheath or thrombus at the catheter tip, 14% had CVAP malposition as the only abnormality, 14% were normal and one patient had extravasation. The CVAP tips were optimally positioned in 70% of patients (distal superior vena cava (SVC), venocava-atrial junction or atrium), while 30% were in a suboptimal position (proximal SVC, brachiocephalic, azygous, or internal jugular vein). Suboptimally positioned CVAPs had a higher incidence of an associated abnormality compared to optimally positioned CVAPs (58% vs. 4% P = 0.001). Only five CVAPs were removed, for extravasation (1), cellulitis (2), and malposition (2). Conclusion: Although the incidence of extravasation was low, venography evaluation could be considered in patients with malfunctioning catheters receiving a vesicant drug to help prevent a potentially significant complication. CVAPs with suboptimally positioned tips had a higher rate of associated abnormalities, emphasizing the importance of proper tip position. No significant financial relationships to disclose.