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IntroductionOutcomes of CML-CP patients treated in clinical trials are frequently perceived to be not representative of those treated outside of clinical trials.Patients and methodsWe investigated the outcomes of patients receiving imatinib outside of a clinical trial (off protocol) or in a clinical trial (on protocol) for CML-CP.ResultsWe identified 65 patients treated with imatinib off protocol and 71 patients treated on protocol with standard-dose imatinib. The overall complete cytogenetic response (CCyR) rate was 83% for patients treated on and off protocol. CCyR rates 12 months after initiation of imatinib were not statistically different (61% vs. 66%, respectively; P = .15). Patients treated off protocol had similar rates of overall major molecular response (72% vs. 73%) compared with the patients treated on protocol. The 5-year event-free survival rates were 84% and 86% for off and on protocol patients, respectively. There was also no significant difference in 5-year transformation free survival (94% vs. 96%) and overall survival (96% vs. 90%).ConclusionThese results suggest that patients with CML treated outside of a clinical trial might have the same excellent outcome as those treated in a clinical trial provided they are followed with the same rigor.

Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.

We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis.

BackgroundThe combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced improved response rates and a prolonged survival in patients with chronic lymphocytic leukemia (CLL). However, its therapeutic power is counterbalanced by significant hematologic toxicity. Persistent and new-onset cytopenia after the completion of FCR raise concern about disease recurrence, the development of therapy-related myeloid malignancies (TRMM), and infections.MethodsA total of 207 patients with CLL who achieved complete response, complete response with incomplete bone marrow recovery, or nodular partial remission were analyzed after frontline FCR therapy.ResultsThree months after the completion of therapy, 35% of patients had developed grade 2 to 4 cytopenia (according to Common Terminology Criteria for Adverse Events [version 4.0]). Factors found to be associated with cytopenia at 3 months after therapy were older age, advanced Rai stage disease, and lower baseline blood counts. Moreover, patients with cytopenia were less likely to have completed 6 courses of therapy with FCR. At 6 months and 9 months after therapy, the prevalence of grade 2 to 4 cytopenia was 24% and 12%, respectively. No differences in progression-free survival and overall survival were noted between cytopenic and noncytopenic patients or between patients with persistent and new-onset cytopenia. The prevalence of TRMM was 2.3% and did not differ significantly between cytopenic and noncytopenic patients or between those with persistent and new-onset disease. Late infections were more common in patients who were cytopenic at 9 months (38%) and were mostly bacterial (67%).ConclusionsCytopenia after the completion of therapy is a common complication of frontline FCR that improves over time, particularly for new-onset cases. The presence of persistent cytopenia (lasting up to 9 months after the completion of therapy) should not raise concern about CLL recurrence of the development of TRMM, but should encourage surveillance for bacterial infections for an additional 9 months.

The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ≤10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).

Advances in the genetic and molecular characterizations of leukemias have enhanced our capabilities to develop targeted therapies. The most dramatic example of targeted therapy in cancer to date is the use of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI), which has revolutionized the treatment of chronic myeloid leukemia (CML). Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target, transforming the prognosis of patients with CML. In contrast, acute myeloid leukemia (AML) is an extremely heterogeneous disease with outcomes that vary widely according to subtype of the disease. Targeted therapy with monoclonal antibodies and small molecule kinase inhibitors are promising strategies to help improve the cure rates in AML. In this review, we will highlight the results of recent clinical trials in which outcomes of CML and AML have been influenced significantly. Also, novel approaches to sequencing and combining available therapies will be covered.

BackgroundDecitabine is standard therapy in patients with myelodysplastic syndrome (MDS). Current recommendations suggest a dose of 20 mg/m(2) intravenously (IV) daily for 5 days every 4 weeks. However, this therapy is associated with frequent grade 3/4 hematologic toxicity, requiring dose delays and/or dose reductions (DD/DR).ResultsWe investigated the outcomes of 122 patients with MDS who had DD/DR of frontline decitabine therapy. Sixty-five patients (53%) had DR by at least 25% or DD (defined as a delay beyond 5 weeks between cycles). Thirty-five patients (29%) underwent DD/DR after achieving best objective response, 30 patients (25%) underwent DD/DR before best objective response, and 57 (54%) patients had no DD/DR. There was a trend for more durable responses in favor of patients requiring DD/DR after the achievement of best objective response (median not reached) (P = .161). Overall survival rates were significantly higher for patients who had DD/DR after best objective response compared with those who had DD/DR before best objective response or those with no DD/DR (30 vs. 22 vs. 11 months, respectively; P < .001). Progression-free survival (PFS) rates also trended higher for those with DD/DR after best objective response (median not reached) compared with those who required DD/DR before best objective response (median of 15 months) (P = .285).ConclusionDD/DR may be safely accomplished once the patient has achieved best objective response (preferably complete remission [CR]) without impacting outcome. Prospective evaluation of an approach conceived of a loading dose for induction of a best objective response followed by a maintenance schedule is to be considered.

B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy.

PurposeRelapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT).Patients and methodsSixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi).ResultsThe CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%).ConclusionHigh-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

Background: Acute kidney injury (AKIis a common complication in the treatment of patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS), but, to the authors' knowledge, its clinical relevance has not been detailed to date. The objective of the current study was to identify the incidence, predictors, and outcome for AKI in patients with AML and HR-MDS.Methods: Data were analyzed from 537 patients with AML or HR-MDS undergoing induction chemotherapy from 1999 to 2007. Predictors for AKI were identified by logistic regression. Eight-week mortality of patients was estimated by the Kaplan-Meier method stratified by the RIFLE criteria, a novel multilevel classification system for AKI based on the percent rise in serum creatinine from baseline (Risk, >50%; Injury, >100%; and Failure, >200% or requiring dialysis).Results: A total of 187 patients (36%) developed AKI. Significant independent risk factors for AKI included the following: age >/=55 years (odds ratio [OR], 1.8), mechanical ventilation (OR, 16), use of vancomycin (OR, 2.3), diuretics (OR, 3.0), amphotericin B lipid formulation (OR, 2.7), vasopressors (OR, 4.9), leukopenia (OR, 1.9), hypoalbuminemia (OR, 1.4), and use of non-fludarabine-based chemotherapy (OR, 2.7). The 8-week mortality rates were 3.8%, 13.6%, 19.6%, and 61.7% for the non-RIFLE, Risk, Injury, and Failure categories, respectively. Patients requiring dialysis (8%) had a median survival of 33 days. Survival of patients who achieved complete remission was favorable, regardless of degree of AKI.Conclusions: The RIFLE classification for AKI appears to have prognostic utility in predicting mortality in patients with AML or HR-MDS. Relatively mild elevations in creatinine are associated with higher mortality. Strategies to avoid nephrotoxic drugs or fluid overload may be of benefit. Cancer 2010. (c) 2010 American Cancer Society.

Objective: There are significant disparities in outcomes among Hispanic patients with acute lymphoblastic leukemia (ALL). Recent studies have demonstrated favorable outcomes of pegaspargase‐containing ALL regimens (PEG‐CAR) in young adults however, outcomes in Hispanic ethnicity continue to be underreported. Methods: We evaluated outcomes of newly diagnosed, adult B‐cell ALL Hispanic and non‐Hispanic patients consecutively treated with a PEG‐CAR or HyperCVAD between January 2011 and November 2022. The primary endpoint was event‐free survival (EFS) while secondary endpoints included cumulative incidence of relapse and overall survival (OS). Results: Among 105 included patients, 48 (45.7%) were treated with a PEG‐CAR and 57 (54.3%) with HyperCVAD. Median age was 38 years (range, 18–75 years), 61% were Hispanic, and 35.2% had poor‐genetic risk. Hispanic patients demonstrated significantly worse 5‐year EFS with a PEG‐CAR compared to that seen with HyperCVAD (HR, 2.58; 95% CI, 1.32–5.04; p =.006) whereas non‐Hispanic patients had better outcomes with PIR (52.4% vs. 42.0%). Hispanic ethnicity (p =.015) and male sex (p =.019) were independent predictors for poor OS. Conclusions: Hispanic patients with B‐cell ALL had worse EFS with a PEG‐CAR as compared with HyperCVAD. Future studies will aim to confirm these findings and establish a tailored treatment approach for this high‐risk population. [ABSTRACT FROM AUTHOR]