Patricia Kropf

Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia.

To the editor: Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) is currently considered the gold standard first-line therapy for chronic lymphocytic leukemia (CLL).[1][1] In an attempt to reduce the neutropenia and maintain the high response rate of standard-dose FCR

Acute myeloid leukemia, version 3.2017: Clinical practice guidelines in oncology

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. This portion of the NCCN Guidelines for AML focuses on management and provides recommendations on the workup, diagnostic evaluation, and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial

BACKGROUND The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. METHODS We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). INTERPRETATION More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. FUNDING Astex Pharmaceuticals and Stand Up To Cancer.

Spontaneous graft versus host disease occurring in a patient with multiple myeloma after autologous stem cell transplant

Graft versus host disease (GVHD) is a common complication of allogeneic transplant. Acute GVHD primarily affects the skin, liver, and GI tract generally within the first 100 days after transplant. GVHD following an allogeneic transplant occurs as a result of donor T-cell recognition of host alloantigens. In contrast, patients undergoing ASCT are not subjected to the genetic disparity that occurs with allogeneic transplant, and in principal, should not develop this proinflammatory response. A clinical syndrome, however, has been described in patients following autologous transplant that shares the same features as GVHD occurring in recipients post-allogeneic transplant [1-3]. Previously reported cases have described skin, liver, and GI tract manifestations consistent with what is seen in allogeneic GVHD. Biopsies of the skin and GI tract mucosa have demonstrated similar histological features as well. Interestingly, the majority of reported cases seem to occur in patients with multiple myeloma undergoing consolidative ASCT. Historically, however, these patients have been described as having a relatively benign course with mild skin rash, nausea, vomiting, and/or diarrhea that is responsive to immunosuppression. In this article, we present a case of fatal, spontaneous GVHD in a patient with multiple myeloma following ASCT.

DNA Hypomethylating Drugs in Cancer Therapy

Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next‐generation hypomethylating agent, could be useful in treating such patients.

Donor Lymphocyte Infusion in Hematologic Malignancies—Good to be Fresh?

BACKGROUND Donor lymphocyte infusion (DLI) has been used with variable success in a variety of hematologic malignancies. PATIENTS AND METHODS We conducted a retrospective analysis of all patients who were treated with DLI for persistent or relapsed disease at the Temple University Bone Marrow Transplant Unit from July 1, 1993 to December 31, 2013 to evaluate the effect of the type of DLI (fresh vs. cryopreserved) on event-free survival (EFS) and overall survival (OS). Median follow-up was 64.8 months (range, 0.3-142.6 months). RESULTS We found that EFS and OS were similar between patients receiving cryopreserved cells and those receiving fresh DLI (median OS for cryopreserved cells, 0.39 years; median OS for fresh cells, 0.32 years; P = .793; median EFS for cryopreserved cells, 0.410 years; median EFS for fresh cells, 0.420 years; P = .4264). In the setting of relapsed disease, treatment with any chemotherapy regimen before receiving DLI did not significantly impact OS (n = 63; P = .2203) or EFS (n = 40; P = .542). A subgroup analysis limited to patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (32 patients) showed that differences in OS and EFS between cryopreserved and fresh DLI approached significance (median OS for cryopreserved cells, 0.34 years; median OS for fresh cells, 0.17 years; P = .16; median EFS for cryopreserved cells, 0.37 years; median EFS for fresh cells, 0.094 years; P = 0.11). CONCLUSION We conclude that the use of fresh cells versus cryopreserved cells does not have an impact on outcomes, and selected patients can achieve long-term survival with DLI for treatment of relapse after transplantation, although the overall outcomes remain dismal.

Splenic irradiation for splenomegaly: A systematic review

Splenic irradiation (SI) is a palliative treatment option for symptomatic splenomegaly (i.e. for pain, early satiety, pancytopenia from sequestration) secondary to hematologic malignancies and disorders. The purpose of the current article is to review the literature on SI for hematologic malignancies and disorders, including: (1) patient selection and optimal technique; (2) efficacy of SI; and (3) toxicities of SI. PICOS/PRISMA methods are used to select 27 articles including 766 courses of SI for 486 patients from 1960 to 2016. The most common cancers treated included chronic lymphocytic leukemia and myeloproliferative disorders; the most common regimen was 10Gy in 1Gy fractions over two weeks, and 27% of patients received retreatment. A partial or complete response (for symptoms, lab abnormalities) was obtained in 85-90% of treated patients, and 30% were retreated within 6-12months. There was no correlation between biologically equivalent dose of radiation therapy and response duration, pain relief, spleen reduction, or cytopenia improvement (r2 all <0.4); therefore, lower doses (e.g. 5Gy in 5 fractions) may be as effective as higher doses. Grade 3-4 toxicity (typically leukopenia, infection) was noted in 22% of courses, with grade 5 toxicity in 0.7% of courses. All grade 5 toxicities were due to either thrombocytopenia with hemorrhage or leukopenia with sepsis (or a combination of both); they were sequelae of cancer and not directly caused by SI. In summary, SI is generally a safe and efficacious method for treating patients with symptomatic splenomegaly.

Burden of Tyrosine Kinase Inhibitor Failure in Patients with Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) have been extremely effective at inducing remissions and slowing down the progression of chronic myeloid leukemia (CML) resulting in a significant reduction in morbidity and mortality. Most patients with CML must remain on TKIs indefinitely and many experience resistance or intolerance to TKIs requiring a switch to a second-line TKI, third-line TKI or more. The purpose of the current review is to examine the underlying factors and subsequent economic and quality of life burdens associated with TKI failure. We discuss the definitions and rates of TKI failure in CML and the extent to which mutations and non-adherence are associated with TKI failure. We also review the few studies that have examined economic and patient outcomes associated with TKI failure and we suggest avenues for future research examining the consequences of TKI failure.

Healthcare utilization and costs associated with tyrosine kinase inhibitor switching in patients with chronic myeloid leukemia.

Abstract Differences in healthcare utilization and costs were examined in chronic myeloid leukemia (CML) patients experiencing first-, second- and third-line tyrosine kinase inhibitor (TKI) therapy. Three CML cohorts were identified from the Truven Health MarketScan® database: No-Switch Cohort (NSc) = did not switch from first-line; One-Switch Cohort (OSc) = switched from first- to second-line only; Two-Switch Cohort (TSc) = switched to second- and then third-line. A total of 3510 patients were identified (mean = 54%; age = 55.8 years). NSc comprised 81% of the sample, OSc comprised 15% and 4% were in the TSc. First-line utilization/costs were significantly higher in the OSc/TSc compared to the NSc. Second-line hospital/outpatient visits and costs were higher in TSc compared to OSc. TSc experienced a significant cost increase from first- to second-line (