bluuebunny/crossref_metadata_2025 huggingface dataset:
Black box warning on lenalidomide-associated venous thromboembolism (VTE) in off-label setting: A preemptive and unusual safety initiative
Authors: Angelotta C. , Lurie A. J. , Yarnold P. R. , Singhal S. , Mehta J. , Lyons E. A. , Bennett C. L.
Published: March 2020

6074

Background: Half of cancer therapies are used off-label, but regulations prohibit package inserts from describing toxicities that occur only in these settings. In 2003, RADAR reported VTE rates of 20% to 62% when thalidomide, approved for leprosy treatment, was used off-label (with dexamethasone) for multiple myeloma. In 2005, the Connecticut attorney general requested that a black box warn of high rates of VTE when thalidomide is used off-label. Subsequently, the thalidomide analogue, lenalidomide, received FDA approval as a myelodysplasia therapy. In phase II/III trials, multiple myeloma response rates were 60% to 92% with lenalidomide/dex therapy. Methods: Published literature, abstracts, and package inserts were reviewed for VTE rates in lenalidomide-treated multiple myeloma. Results: VTE rates were 8.5% to 75% in multiple myeloma treated with lenalidomide and dex or erythropoietin; rates were <3.4% when aspirin prophylaxis was added. The FDA approved package insert for lenalidomide preemptively includes a black box warning describing high VTE rates with off-label use of lenalidomide and advises physicians that VTE prophylaxis should be considered, although the effectiveness of various prophylaxis regimens is unknown. Conclusions: Six months after the attorney general requested that a black box warning describe high VTE rates with off-label use of thalidomide, the manufacturer preemptively included an analogous black box warning in the package insert for the thalidomide analogue, lenalidomide, but did not include similar warnings for this toxicity in the package insert for thalidomide. The FDA should require that package inserts describe severe toxicities that commonly occur with off-label use of cancer therapies. This is especially important for severe class-related toxicities such as lenalidomide- and thalidomide- associated VTE.

[Table: see text]

No significant financial relationships to disclose.
Dose banding of chemotherapy doses at the Juravinski Cancer Centre
Authors: Hirte H. W. , Kagoma S. , Zhong L. , Collins I. , Burns D. , Rand C. , Simpson T. , Snider A.
Published: March 2020

6099

Background: As the number and complexity of chemotherapy regimens increase, the demands on pharmacy services to reduce chemotherapy preparation and checking times continues to increase. Dose banding, a system whereby doses of intravenous cytotoxic drugs calculated on an individual basis are rounded up or down to predetermined standard doses (the maximum variation of the adjustment between standard dose and doses constituting each band is 5% or less) was identified as a strategy that could be used to address some of the issues around time pressures to help reduce patient waiting times for treatment. Methods: The project consisted of 3 phases; Phase I - literature review to identify dose banding publications; Phase II - selection of drugs to be banded for the pilot. The two drugs selected were 5FU and leukovorin, and Phase III - Time studies pre-, interim and post dose banding implementation to determine drug dispensing time and patients’ wait time for pharmacy related procedures. This occurred for a 2 week period (10 working days) either prior to implementation (pre- 819 patients studied), 4 days after implementation (interim - 854 patients studied) and 4 weeks after implementation (post - 785 patients studied). Results: Drug dispensing time did not decrease with dose banding (pre- 7.9 min, interim - 7.6 min and post - 9.4 min). However, the average patient wait time decreased after piloting the dose banding project (pre - 31.6 min, interim 23.7 min, and post - 27.8 min). The percentage of doses that were banded were 37.8% in the interim time study and 58.2% in the post time study. Conclusions: Although dose banding did not reduce dispensing time in this study, likely because the preparation for dispensing 5FU and leukovorin syringes is normally very simple and quick, patient’s wait time for pharmacy related procedures did decrease. This was probably due to contributions of other factors in the pharmacy process. A reduction in dispensing time could likely be achieved if more complex regimens were considered for dose banding. Dose banding could be used to increase capacity within the chemotherapy suite on the day of administration. It also allows for a better work schedule and increases efficiencies within the chemotherapy preparation and administration areas. (Sponsored by funds from Cancer Care Ontario)

No significant financial relationships to disclose.
Misunderstanding of prostate cancer (CaP) among African American (AA) men of lower socioeconomic status (Lo-SES)
Authors: Nelson E. M. , Fraser G. , Connors A. F. , Barry M. J. , Krahn M. , Conaway M. R. , Bashore R. , Wolf A. , Kilbridge K. L.
Published: March 2020

6114

Background: CaP disproportionately affects AA men. The objective of this investigation was to assess understanding of the prostate and CaP among Lo-SES, predominantly AA men. Methods: We performed cross sectional, semistructured interviews of 105 men, age 40 and older, in two low-income medical clinics. CaP knowledge was assessed using a subset of questions by Mercer et al. Can J of Public Health 88(5):327, 1997. Patients were shown two male anatomic figures and asked to identify the prostate, bladder, bowels, and penis: 1) Please point to the _____ on the picture of the man. 2) What does the ____ do? Patients’ understanding of sexual, urinary, and bowel function was evaluated using semi-qualitative methods coded by two independent investigators. Demographic data were collected and literacy measured using REALM. Results: Patients’ median age was 58 and 87% self-identified their race as AA. Median annual household income was $16,000. Median reading level was 4th-6th grade. Although 87% of patients had heard of the prostate, only 24% could locate the prostate, and 3% could explain prostate function. Because many men learn about the prostate in the context of CaP screening during physical exam, 23% of patients thought the prostate was synonymous with prostate cancer, 15% of patients believed the prostate is located in the rectum and 4% confused prostate cancer with colorectal cancer. Prostate cancer knowledge was poor and the concept of a risk factor was not understood well. Only 7% could name a single risk factor for CaP including 3% who named race. Just 22% of men cited surgery or radiation therapy as treatments for CaP and 11% could name a side effect of early CaP treatment. Domain confusion was common: 43% of patients confused bowel function with urinary function, 21% confused urinary with sexual function, and 20% confused bowel with sexual function. Conclusions: Baseline understanding of CaP, anatomy, bowel, urinary, and sexual function is poor among older, lo-SES AA men. Substantial patient education is required for CaP screening and treatment efforts in this population with consideration for low literacy.

[Table: see text]
Cost-effectiveness of lenalidomide in treating patients with transfusion-dependent myelodysplastic syndromes (MDS) in the United States
Authors: Goss T. F. , Szende A. , Schaefer C. P. , Totten P. J. , Wang M. Y. , List A. F.
Published: March 2020

6128

Background: Lenalidomide is approved for treatment of patients with transfusion-dependent Low- or Intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. We evaluated the cost-effectiveness (CE) of lenalidomide versus best supportive care (BSC) in these MDS patients. Methods: We used a decision analytic model to compare costs and outcomes of lenalidomide [with BSC, but no erythropoietin (EPO)] vs BSC (with EPO) over 1 year. Data were obtained from a phase II trial for lenalidomide (MDS-003). Data for BSC were based on a study that included TD MDS patients (efficacy and transfusion requirements) and the placebo arm of a randomized MDS trial (safety). The model compared results of MDS-003 and a theoretical cohort with similar characteristics (TD, EPO response and IPSS low or int-1 score). Outcome measures were rate and duration of response (TI time gained). The model incorporated costs (from Medicare schedules; 2005 US$) of meds, transfusions, lab tests, office visits and other resources. Results: Response rate (TI) was 67.0% in the lenalidomide group vs 32.8% for responders with no prior EPO experience in the BSC group. Lenalidomide therapy led to an estimated 0.53 transfusion-free and 0.23 quality-adjusted life year (QALY) gain compared to BSC at 1 year. The costs of lenalidomide therapy were largely offset by reduced blood transfusion and EPO costs with 1-year total treatment costs estimated at $62,138 vs $53,965 for BSC. We estimated incremental CE of lenalidomide vs BSC per TI year and QALY gained using one-way sensitivity analyses reflecting uncertainty in parameter estimates. The incremental CE ratio for lenalidomide vs BSC varied between $5,742 - $20,940 per TI year gained and $13,216 - $47,758 per QALY gained, suggesting acceptable ranges of CE for a new therapy. Conclusions: Results suggest that treating Low- or Int-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or w/o additional cytogenetic abnormalities with oral lenalidomide results in reduced transfusion requirements vs BSC. Research to confirm these results with data from ongoing randomized trials is warranted.

[Table: see text]
A cost analysis of practicing oncology via telemedicine
Authors: Doolittle G. C. , Spaulding A. O. , Williams A. R.
Published: March 2020

6143

Background: The University of Kansas Medical Center (KUMC) has offered oncology services via interactive tele-video (ITV) to patients in rural Kansas for over a decade. A KUMC oncologist utilizes ITV technology to connect with patients at Hays Medical Center (HMC), which is approximately 265 west of KUMC. The technology enables the oncologist to conduct a complete patient visit without being in physical proximity to the patient. To date, two cost-tracking studies have been conducted to determine expenses associated with the tele-oncology practice. A third study recently analyzed costs incurred during fiscal year 2005 (FY05). Methods: In order to determine the costs of the practice during FY05, HMC and KUMC expenses were monitored for oncology services rendered via telemedicine. An analysis revealed expenses common to a traditional oncology practice and additional expenses unique to a telemedicine practice. Administrative support staff salaries, the oncologist’s contract fees, and nursing staff salaries made up the majority of the traditional practice-related expenses. Costs unique to a tele-oncology practice were those associated with technology including expenses for telemedicine equipment, telecommunication charges, and technician time. Results: Expenses for the tele-oncology practice on the KUMC side totaled $22,848, with $7,331 attributed to technology-related costs and $15,517 attributed to practice-related costs. For HMC, $5,803 in technology-related costs and $30,430 in practice-related costs totaled $36,233. At 235 tele-oncology consults and a combined total expense of $59,081 between KUMC and HMC, the FY05 analysis resulted in an average cost of $251 per consult. When compared to prior studies, this shows a substantial reduction in costs related to the practice of telemedicine. Conclusions: The average cost of a tele-oncology visit in Kansas has consistently decreased significantly since the practice’s 1995 inception. Analyses have revealed that the costs of providing oncology services via telemedicine are closely tied to utilization, as the majority of the expenses are related to personnel rather than technology. Telemedicine has proven itself to be a cost-efficient alternative to offering regular outreach clinics.

No significant financial relationships to disclose.
Updated results of a phase I study of low dose decitabine and valproic acid (VA) in patients with acute myeloid leukemia (AML): Gene reexpression, demethylation, and clinical response
Authors: Klisovic R. B. , Blum W. , Hackanson B. , Kefauver C. , Liu S. , Liu Z. , Chan K. K. , Plass C. , Grever M. R. , Byrd J. C. , Marcucci G.
Published: March 2020

6515

Background: Decitabine, an inhibitor of DNA methyltransferase (DNMT) enzymes, has activity in myeloid malignancies at doses >1 log below the MTD of 2250mg/m2/course which may be optimal for DNA demethylation and minimize cytotoxicity. Methods: We designed a two step trial for AML patients (pts) to determine: Step 1, the lowest dose of decitabine to induce 100% increase in or re-expression of epigenetically silenced genes in 5/6 pts treated at a dose level; and Step 2, the MTD of the histone deacetylase (HDAC) inhibitor VA given with this dose of decitabine, and whether this MTD or a lower dose leads to 90% decrease in HDAC activity. Results: Decitabine was administered to 17 pts at two dose levels. Pts had relapsed/refractory AML (N=10) or age>60 and ineligible/refused standard therapy (N=7) and ranged in age from 36–83 years. Pts received decitabine at 15–20mg/m2/IV over 1 hr daily for 10 days (d) (3 pts also had VA 15mg/kg on days 5–21), every 28 d. Mean plasma decitabine Cmax (by a validated LC-MS/MS method) was 93 ng/ml (N=7). 10/13 pts had at least 100% increase in expression of p15 or estrogen receptor (ER, including 5/6 given 20mg/m2/d decitabine alone), and all 10 had clinical response. Of the 3 pts who did not have increased gene expression none responded. Western blotting showed depletion of DNMT protein in 4/6 pts. Bisulfite sequencing of the promoter region of ER confirmed that decitabine induced >50% decrease in methylation in the only pt yet examined (p<0.001). 9/14 pts had decrease in global DNA methylation as measured by LC-MS/MS. 10/15 pts had clinical benefit: 6 pts had clinical response, 2 with CR (1 with t-AML) and 4 with CRi (1 with a 20yr history of P. vera); 4 pts had clinical improvement-1 met all CR criteria except for BM disease by flow, 1 had platelet >100K, 2 had stabilization of disease for 4–6 months. Conclusions: We demonstrated clinical activity of low dose decitabine associated with decreased levels of the DNMT1 target and increased or re-expression of epigenetically silenced genes. Combination of decitabine at 20mg/m2/d with VA (Step 2) has begun; complete clinical results, gene re-expression/ demethylation, and histone deacetylation data will be presented. (NCI U01 CA 76576–05)

[Table: see text]
Pharmacologically derived schedule of flavopiridol has significant efficacy in refractory, genetically high risk chronic lymphocytic leukemia (CLL)
Authors: Byrd J. C. , Lin T. S. , Dalton J. T. , Phelps M. , Fischer B. , Moran M. , Blum K. , Rovin B. , Colevas A. D. , Grever M. R.
Published: March 2020

6516

Background: Promising pre-clinical activity with flavopiridol in CLL was followed by disappointing clinical trial results. Differential protein binding of flavopiridol in pre-clinical studies may have misdirected the target concentration and administration schedule in CLL trials. Methods: We initiated a phase I study based on pharmacokinetic (PK) modeling showing that 1.5–2.0 μM flavopiridol for 4–6 hours was necessary for anti-CLL activity in vitro with 10% human serum. A 30 minute loading dose followed by a 4 hour infusion every 4 of 6 weeks was pursued. Eligibility included refractory/relapsed CLL, intact organ function, and performance status of ≤ 2. Results: Fifty-six pts have been enrolled ( Table ) with a median of 4 prior therapies, and most fludarabine-refractory. Dose-limiting toxicity in cohort 2 was tumor lysis syndrome (TLS). Cohort 1 was expanded with aggressive TLS prophylaxis. Of 20 pts in cohort 1, 8 (40%) had a partial response (PR) with a median response duration exceeding 12 months. The 0.5 and 4.5 hr Cmax were 2.08 μM and 0.96 μM. PK modeling showed that higher dose in the 4-hr infusion would achieve desired 4.5 hr Cmax. This escalation was done in cohorts 3 and 4 ( Table 1 ) with acceptable toxicity. In cohort 3, 19 pts enrolled with 14 pts being dose escalated. Improved cytoreduction was seen in most pts with dose escalation. Ten (53%) of pts attained a PR. The 0.5 and 4.5 hr Cmax was 1.95 μM and 1.54 μM in cohort 3;dose escalation continues in cohort 4. WBC of ≥ 200 × 109/L was associated with TLS (5 of 8 pts) versus those with WBC < 200 × 109/L (1 of 34 pts). As such, cohort 4 excludes pts with WBC ≥ 200 × 109/L for safety. Currently there are 14 pts in cohort 4 with only 1 case of TLS. Response assessment for cohort 4 is underway; activity appears similar to cohort 3. Conclusions: Flavopiridol with this PK directed schedule has significant clinical activity independent of the presence of del(17p13.1) and is one of the most active agents in clinical trials for CLL.

[Table: see text]

No significant financial relationships to disclose.
Proteomic signatures of acute myeloid leukemia (AML) distinguishes different outcome groups across cytogenetics and identified potential therapy targets
Authors: Tibes R. , Qiu Y. , Coombes K. , Hennessy B. , Kantarjian H. , Giles F. , Estey E. , Mills G. , Kornblau S.
Published: March 2020

6523

Background: Cytogenetics (CG) guide AML treatment but reliable markers predicting response and relapse within CG groups are missing. We therefore determined whether functional proteomic signatures can classify AML into groups with different outcomes and risk of relapse. Method: Using Reverse Phase Protein Array, total and phospho-site specific expression of 37 proteins in 73 primary AML was measured. Outcomes in the set were comprised equally of primary refractory (PR), relapsed (Rel) and continuous complete remission (CCR) patients. Cell lysates were spotted on nitrocellulose coated slides, probed with validated antibodies, expression intensities were quantified, data was standardized and analyzed for correlations using different clustering approaches. Results: Unsupervised hierarchical clustering based on Pearsons’ correlation distance yielded 4 large clusters. Subsequent perturbation bootstrap re-sampling arranged samples into four classes that correlated with initial response to therapy and risk of relapse (see Table ). Protein profiles in each of he 4 classes differed. Cytogenetic marker distribution were similar across the 4 clusters. Class 1 and 4 demonstrated a similar predictive value of patient outcome as cytogenetics. In classes at highest risk of relapse (2, 3) different proteins were predictive of response. In class 2, the most discriminatory proteins predicting CCR were elevated AMPK, p27, 4-EBP1, BclXL. In class 3, relapsed patients had elevated PTEN, phospho-Stat3, total Stat3, and phospho-PKCα compared to CCR patients. Conclusion: Pretreatment protein expression signatures divide AML into classes that predict for initial achievement of CR and subsequent relapse independent of CG. Poteomic profiling may suggest potential therapy targets as opposed to CG or transcriptional profiling. These preliminary results need to be confirmed in formal training and test sets prior to changing patient management.

[Table: see text]

No significant financial relationships to disclose.
Dasatinib (D) in patients with accelerated phase chronic myeloid leukemia (AP-CML) who are resistant or intolerant to imatinib: Results of the CA180005 ’START-A’ study
Authors: Talpaz M. , Apperley J. F. , Kim D. W. , Silver R. T. , Bullorsky E. O. , Cheng S. , Iyer M. , Guilhot F.
Published: March 2020

6526

Background: Dasatinib (D) (BMS-354825) is an oral multi-targeted kinase inhibitor with preliminary evidence of efficacy in a previously reported phase I study. START A is an open-label study of dasatinib in AP-CML pts who were imatinib resistant (IM-R) or imatinib intolerant (IM-I). Methods: A total of 192 pts were enrolled between December 2004 and Jun 2005 in 39 centers worldwide. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalations to 100 mg BID were allowed for poor initial response and reductions to 50 or 40 mg BID for persistent toxicity. Evaluations were weekly blood counts and monthly bone marrow evaluation including cytogenetics. The primary endpoint was major confirmed (maintained at least 4 weeks) hematologic response (MaHR) in IM-R pts. Results: The first 107 pts (99 IM-R, 8 IM-I) with at least 6 months of follow-up are currently reported; there were 55 males/52 females; median age 57 years (range 23–86); median time from diagnosis of CML 90.9 months. Prior therapy included IM>600 mg/day in 63 (59%) pts, interferon in 80 (75%) pts. Major cytogenetic response (MCyR) to prior IM was seen in 34 (32%) pts. 56 pts had Bcr-Abl kinase domain mutations. Median duration of therapy was 5.5 months. MaHR was documented in 63 (59%) pts (95% CI: 49–68) with complete hematologic response in 35 (33%) and no evidence of leukemia in 28 (26%). In IM-R pts, the MaHR rate was 59%. MCyR was documented in 33 (32%) pts (95% CI: 22.9–41.6); complete in 23 (22%), partial in 10 (10%). MaHR were seen in pts with Bcr-Abl mutations and in pts who never responded to IM. Molecular response analysis is ongoing. There were 15 disease progressions including one loss of MaHR. Myelosuppression was significant with grade 3–4 thrombocytopenia and neutropenia in 79% and 69% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent were diarrhea (46%), peripheral edema (27%), pleural effusion (16%), rash (8%), and GI hemorrhage (7%). Conclusions: Dasatinib was very effective in IM-R pts with AP-CML with high rates of durable MaHR and MCyR. Data on all 192 pts will be presented at the meeting.

[Table: see text]
Dasatanib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): The CA180015 ‘START-L’ study
Authors: Coutre S. , Martinelli G. , Dombret H. , Hochhaus A. , Larson R. , Saglio G. , Gollerkeri A. , Apanovitch A. , Ottman O. G.
Published: March 2020

6528

Background: Dasatinib (D) (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Preliminary data from a phase I study suggest high efficacy of D in IM pretreated pts. Methods: START L is an open label phase II study of D in IM-R or IM-I pts with LB-CML and Ph+ALL conducted at 42 centers worldwide. D was given orally, 70 mg twice a day (bid), with escalation to 100 mg bid for poor response or reductions to 50 mg and 40 mg bid for toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. The primary endpoint was confirmed (sustained for at least 4 weeks) major hematologic response (MaHR) rates. Results: From January to June 2005, 101 pts were accrued. Data are available on the first 78 treated pts (42 LB-CML, 36 Ph+ALL). Of the 42 LB-CML pts, 37 were IM-R, 52% were male with median (med) age of 47 years. Prior therapy included IM >600 mg/day in 52% and stem-cell transplant (SCT) in 33% of pts. Med baseline platelet (plt) count was 32.5/nl, med BM blasts were 82%, Bcr-Abl mutations were seen in 48%, and extramedullary disease (EMD) was seen in 29% of pts. The D dose was reduced in 14%, temporarily interrupted in 33%, and escalated in 26% of pts. At 6-months, the MaHR rate was 31% including 26% complete hematologic response (CHR), the MCyR rate was 50%, and 17% of pts remained on study. Of the 36 Ph+ALL pts, 34 were IM-R, 64% were male with med age 46 years. Prior therapy included IM> 600 mg/day in 47% and SCT in 42% of pts. Baseline plt count was 53.5/nl, med BM blasts were 69%, Bcr-Abl mutations were seen in 47% and EMD was seen in 31% of pts. The D dose was reduced in 28%, temporarily interrupted in 39%, and escalated in 47% of the pts. At 6-months, the MaHR rate was 42% including 31% CHR, the MCyR rate was 58%, and 33% pts remained on study. Among all 78 pts, grade 3–4 thrombocytopenia and neutropenia was seen in 82% and 76% of pts, respectively. The most frequent D-related non-hematologic toxicities were diarrhea (30%), nausea (23%), fatigue (19%), rash (17%) and pleural effusion (13%). Conclusions: D is active in IM pretreated LB-CML and Ph+ALL pts. Data on all 101 pts will be presented at the meeting.

[Table: see text]
Dasatinib (BMS354825), a dual Src-Abl inhibitor, is active in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML) following treatment failure with imatinib mesylate and AMN107
Authors: Estrov Z. , O’Brien S. , Giles F. , Garcia-Manero G. , Borthakur G. , Ravandi F. , Sams I. , Nicaise C. , Kantarjian H.
Published: March 2020

6530

Background: Dasatinib is a dual Src-Abl kinase inhibitor which is 300 fold more potent than imatinib and 20-fold more potent than AMN107 (a selective potent Bcr-Abl kinase inhibitor). Dasatinib also inhibits Src which may overcome CML resistance. Methods: Study Aims: To report the experience with dasatinib in patients who develop CML failure post AMN107. Patients and Methods: All patients on the ongoing dasatinib studies at our institution were reviewed for prior therapy/response to AMN107 and outcome on imatinib. Results: 16 patients with Ph+CML following treatment failure with AMN107 received dasatinib. All patients had previously shown hematologic resistance to imatinib. AMN107 failure was due to hematologic resistance in all 16 pts. Median age was 60 years (range 22 to 76 years); median follow-up on dasatinib is 3 months (range <1 to 9 months). CML phase was chronic in 2, accelerated in 6, blastic in 6, and second chronic/accelerated in 2. Abl mutations were found in 7/16 patients before dasatinib therapy: G250E+F359L, G250E, Y253F, Y253H, H396R (1 patient each), T315I (2 patients). All patients received dasatinib 70 mg orally BID (n = 10), 140 mg single daily dose (n = 5), or 120 mg orally BID (n = 1). Responses were observed in 5 of 7 patients with mutations including 4/4 with P loop mutations and 1/2 with other mutations; the 2 patients with T315I had resistant disease. Conclusions: Dasatinib is active in patients with CML resistant to both imatinib and AMN107.

[Table: see text]

[Table: see text]
The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia
Authors: Buccisano F. , Maurillo L. , Del Poeta G. , Del Principe M. , Mazzone C. , Fraboni D. , Panetta P. , Gattei V. , Lo Coco F. , Amadori S. , Venditti A.
Published: March 2020

6533

Background: Multiparametric flow-cytometry is frequently used to assess the levels of minimal residual disease (MRD) in acute myeloid leukemia (AML) patients achieving complete remission after intensive chemotherapy. In our previous experience, MRD negativity after consolidation cycle, as defined by a level of bone marrow residual leukemic cells ≤3.5x10−4, was associated with a significantly longer relapse free survival (RFS) and overall survival (OS). The aims of the present study were to confirm, in a larger series of patients, the prognostic relevance of the post consolidation MRD assessment and to validate the threshold of 3.5x10−4. Methods: 100 patients affected with AML were entered into the EORTC/GIMEMA protocols AML10/AML12 (age <61 yrs) or AML13/AML15 (age >61 yrs), consisting in intensive induction and consolidation cycles. Median age was 52 years (range 18–78), all FAB subtypes were represented with the exception of APL cases. A Maximally Selected Rank Statistic analysis was used to select the best threshold. Results: The statistical test confirmed that the level of 3.5×10−4 residual leukemic cells was the most significant in discriminating categories of risk. In fact, levels of MRD measured at the post-consolidation time-point identified 2 distinct subgroups: 36 patients MRD negative and 56 MRD positive. MRD negative patients had a better outcome in terms of relapse rate (P<0.001), OS (P=0.039) and RFS (P=0.008), regardless of MRD status after induction. In fact, patients entering MRD negativity only after consolidation showed the same outcome as those achieving early negativity after induction. The multivariate analysis, including karyotype, age, MDR1 phenotype and post induction and post consolidation MRD levels, indicated that the post-consolidation MRD status was an independent factor affecting relapse rate (P<0.001), OS (P=0.039) and RFS (P=0.008). Conclusions: We conclude that 1) the threshold of 3.5x10−4 is valid in discriminating risk categories in AML; 2) MRD assessment at post-consolidation check-point is critical to predict disease outcome. The incorporation in clinical trials of flow-cytometric MRD determination may allow a more accurate risk stratification of AML patients.

No significant financial relationships to disclose.
Apoptotic disseminated tumor cells reflect response to primary chemotherapy in breast cancer
Authors: Fehm T. N. , Becker S. , Wallwiener D. , Gebauer G. , Solomayer E.
Published: March 2020

654

Background: Primary chemotherapy (pCHT) is an established method to reduce tumor size (downstaging) in breast cancer patients before performing breast conserving therapy. The consequences of pCHT on tumor cell dissemination in these patients are not known. The aim of this study was to investigate (1) the incidence of disseminated tumor cells (DTC) including apoptotic DTC in patients with breast cancer after primary chemotherapy and (2) its correlation with pathological therapy response. Methods: Bone marrow aspiration was performed in 157 patients after primary chemotherapy. Cytokeratin-positive cells were detected by immunocytochemistry using the AB45-B/B3 anti-cytokeratin antibody. For detection of apoptotic tumor cells the antibody M30 (Roche Diagnostics, Germany) was used. M30 reacts with a neo-epitope expressed only after caspase cleavage of CK 18 during early apoptosis. Results: The incidence of disseminated tumor cells in breast cancer patients was 57% (84 of 157 pts) after completion of primary systemic therapy. Tumor dissemination was observed more frequently in patients with no change/progressive disease (NC+PD: 63%) than in those who showed partial (PR) or complete remission (CR) of the primary tumor (PR+CR: 43%) (p<0.05). However, 9 of 23 (40%) patients with complete response were still bone marrow positive. Apoptotic tumor cells were present in 36 of 157 (23%) breast cancer patients. The positivity rate of apoptotic cells was higher in bone marrow positive patients with PR or CR (42%) compared to those with stable disease (SD) (26%). No apoptotic tumor cells were detected in patients with tumor progression (n=5). Conclusions: The pathological therapy response is reflected by the presence of apoptotic tumor cells in the bone marrow of breast cancer patients. However, patients with complete response may still have non apoptotic disseminated tumor cells. Patients with tumor cell dissemination after primary systemic therapy may be benefit from additional secondary adjuvant treatment (e.g. bisphosphonates, antibody based strategies).

No significant financial relationships to disclose.
Low power laser in the prevention of induced oral mucositis in bone marrow transplantation patients
Authors: Antunes H. S. , De Azevedo A. M. , Adão C. E. , Pinheiro C. T. , Pinheiro L. H. , Azevedo R. , Mayhe R. , Matos V. D. , Zângaro R. A. , Ferreira C. G.
Published: March 2020

6541

Background: High-dose chemotherapy followed by bone marrow transplant produces undesirable effects in the oral cavity leading to oral mucositis (OM) that may be a painful and debilitating side-effect. Laser therapy has been used to improve the symptoms and duration of already established OM in this group of patients (pts). Recent data suggest the upfront use of laser therapy may decrease the incidence of OM. Methods: Through the use of upfront LPL as protecting and modulating therapy of the oral mucosa membrane, we evaluated the potential for a reduction in the incidence and/or severity of OM in pts submitted to autologous (AT) or allogeneic (AL) bone marrow transplant (BMT). Sample size was based on estimative of P0 control = 0.6 and a P1 LPL = 0.1, β = 0.1; α= 0.05. From Jan 2004 to May 2005, 38 pts treated at the National Bone Marrow Transplant Center in Rio de Janeiro were randomized into a group of 19 pts that received and a group of 19 that did not receive the application of the preventive LPL from the beginning of the conditioning. The irradiation was used an diode InGaAlP, emiting light at 660 nm wavelenght with output power of 50 mW, giving an energy density of 4 J/cm2. The tip of the laser device touched the oral mucosa. The evaluation of OM was done by different investigators both by WHO and OMAS scale. Results: The male to female ratio was 60.5/39.5%. The median age 37 (19–56). The frequency of AT and AL was 73.7 (15.8% non related) vs 26.3%. In the LPL group 94.8% of pts had OM WHO grade < 2 (including 63.2% with grade 0), whereas in the control group 68.4% of pts had OM grade III and IV (p<0,001). Remarkably the HR for grade II, III and IV OM was 0.41 (CI 95% 0.22–0.75, p = 0,002) and for grade III and IV was 0.07 (CI 95%0.11–0.53, p<0,000). Using OMAS scale by the calculation of ulcerous area, 73.6% of LPL pts presented lesions of 0 to 3 cm2, whereas 73.6% of the control group presented ulcers from 9.1 to 18 cm2 (p=0.003). An agreement was observed among investigators (index of 81.7%) and between WHO and OMAS scale (p<0,001). Conclusion: Our results indicate that the use of upfront LPL in bone marrow transplantation patients is a powerful instrument in reducing the incidence of OM and is now standard in our center.

No significant financial relationships to disclose.
Phase I/II clinical trials for relapsed elderly acute leukemia patients: Importance of performance status at re-induction. A single center retrospective experience
Authors: Van Heeckeren W. J. , Fu P. , Barr P. , Laughlin M. , Tse W. , Lazarus H. , Remick S. , Cooper B.
Published: March 2020

6575

Background: Relapsed/refractory acute leukemia patients (pts) have a poor outcome and should be considered for enrollment on clinical trials. Elderly (≥ 60 yr) acute leukemia patients often are excluded from phase I/II cytotoxic agent re-induction chemotherapy trials due to concerns for treatment-related toxicity. Methods: Pts with relapsed/refractory acute leukemia who were enrolled on three consecutive phase I/II clinical trials at University Hospitals of Cleveland were evaluated for outcome data including complete response (CR), serious adverse events, and overall survival (OS). Outcome data was compared for pts age ≥ 60 yr versus < 60 yr. Pts with ECOG Performance Status (PS) 0 to 3 were eligible and there was no age limitation. Results: Between 1994 and 11/2005, 96 acute leukemia pts median age 60 yr (range 19–78) were enrolled: 29 pts received phase I topotecan-etoposide; 31 pts received phase I fludarabine, carboplatin, and topotecan (FCT); and 37 pts received phase II FCT plus thalidomide. In univariate analysis, PS at therapy initiation, mean # prior treatments, and disease status at time of treatment were not statistically different between older and younger pts ( Table ). Using Kaplan-Meier method, early treatment-related mortality and OS were similar in pts age ≥ 60 yr compared to pts < 60 yr ( Table ). Mean # ≥ grade 3 toxicities and CR also were similar in both groups ( Table ). In univariate (p = 0.001) and multivariate (p = 0.0004) analyses by Cox modeling, pts PS 0–1 had better OS than PS 2–3 (PS 0–1: 30-day survival 98% and 1 yr survival 24% versus PS 2–3: 30-day survival 81% and 1 yr survival 6%). Conclusions: Poor PS is an important negative predictor of outcomes in relapsed/refractory acute leukemia pts. Advanced age should not exclude pts from cytotoxic re-induction chemotherapy trials.

[Table: see text]

No significant financial relationships to disclose.
Reproducibility of the Penn predictive score of tumor lysis syndrome (PPS-TLS) in acute myelogenous leukemia (AML)
Authors: Mato A. R. , Miltiades A. N. , Guo M. , Heitjan D. F. , Carroll M. P. , Loren A. W. , Porter D. L. , Stadtmauer E. A. , Perl A. E. , Luger S. M.
Published: March 2020

6577

Background: In a previous retrospective study of 194 patients undergoing AML induction chemotherapy, we described a TLS predictive model entitled the Penn Predictive Score for Tumor Lysis Syndrome (PPS-TLS). TLS incidence was 9.8%. The PPS-TLS is defined as the sum of the scores for pre-induction lactate dehydrogenase (LDH), uric acid (UA), and gender (see table ). The area under the receiver operator characteristic (ROC) curve for this cohort was 89% (SD 4%). Methods: To validate the PPS-TLS, we retrospectively analyzed a second dataset of 166 AML patients undergoing induction chemotherapy from 2003–2006 at our institution. All patients received TLS prophylaxis. TLS was defined as (i) doubling of baseline serum creatinine (Cr) in association with elevated serum phosphate, UA, or potassium or (ii) elevations in 2 of the above electrolytes within 7 days of initiation of therapy. Potential TLS predictive factors were analyzed for statistical significance. Results: In this new dataset, TLS incidence is 9.6%. Significant in univariate analysis are male sex (OR=6.0, CI 1.31–27.15), Cr (OR=13.0, CI 2.88–58.23), UA (OR=48.6, CI 5.78–408.95), and LDH (OR=1.2, CI 1.03–1.48). In multivariate analysis, LDH (OR=1.3, CI 1.04–1.70) and Cr (OR=6.8, CI 1.48–30.89) remain significant. PPS-TLS scores were calculated and tested for their ability to predict TLS in this dataset. The area under the ROC curve for the PPS-TLS in this dataset was 75% (CI 61%-89%), indicating that the probability that a patient with TLS would have a higher PPS-TLS score than one without TLS is 75%. The current result is not statistically significantly different from the area under the ROC curve in the initial dataset (89%). Conclusions: The PPS-TLS is the first TLS predictive model in AML. The reproducibility of this model is supported by this study. A prospective multisite study is being designed to further validate this model. This analysis may lay the groundwork for the first evidence-based guidelines for TLS monitoring and management in AML.

[Table: see text]

No significant financial relationships to disclose.
Improved outcome for acute lymphoblastic leukemia (ALL) in children and adolescents: Results of the MCP841—A two decades report from a developing country (India)
Authors: Sagar T. G. , Chandra A. , Devarajan S.
Published: March 2020

6586

Background: In the 1970s, survival rates after treatment for ALL in children and young adults (< 25 years) in India were poor. The introduction of a standard protocol (MCP841) and improvements in supportive care led to an increase in the event-free survival (EFS) from <20% to 45–50% at 4 yrs. Results of treatment with protocol MCP841 between 1983–2002 have been briefly reviewed here. The MCP841 reports the first prospective, nonrandomized trial for ALL, in collaboration with NCI-US. The aim of this study was to classify immunophenotypes, to analyze clinical features and laboratory features, and to assess whether this protocol would improve the survival rate. Methods: From Jan. 1983 to Dec. 2002, 566 patients (0–25 years) were diagnosed with ALL were treated on MCP841 protocol with intensive induction, central nervous system (CNS) directed therapy and maintenance therapy. Results: From 1983–1989, 171 patients were enrolled and achieved a complete remission (CR) of 74.8% with 25.1% induction deaths and 47.6% relapsed after remission. During 1989–2002 with improvement in supportive care 395 patients enrolled. 328 (83%) of the patients achieved CR, 45 failed to respond and 59 (11.9%) had drug or disease related death before completing induction therapy. The overall 5-year EFS rate was 38.3%. The 5-year RFS rate was 44.5%. Relapse was noted in 147 of the 328 patients (44.8%). The cumulative incidence of CNS relapse was low. Age and white blood cell count is strongly associated with outcome in Western series, but was not a risk factor for EFS. At univariate and multivariate analysis the most significant determinant of a positive outcome was the achievement of CR. Comparison of patient characteristics with published series from Western nations indicated that patients had more extensive disease at presentation, as measured by WBC, lymphadenopathy and organomegaly. The proportions of ALLs with precursor T-cell immunophenotypes, were also increased. Conclusions: Our strategy to adapt to our population of patients and was effective in improving the EFS. It cannot be assumed that risk factors defined in Western populations are equally appropriate for patient assignment to risk-adapted therapy groups in less affluent countries.

No significant financial relationships to disclose.
The frequency of the JAK2 V617F mutation in patients with polycythemia vera and its correlation with severity of disease
Authors: Silver R. T. , Lee S. , Jones A. V. , Rivera M. , Feldman E. J. , Roboz G. , Ritchie E. , Allen-Bard S. , Cross N.
Published: March 2020

6587

Background: The frequency of the JAK2 V617F mutation in patients with polycythemia vera (PV) has ranged from approximately 65–97% in published reports from different institutions. Moreover, its expression has been variably correlated with certain aspects of the disease. Therefore, we quantified its frequency in patients from our institution, and also determined if its presence correlated with severity or duration of disease. Methods: We used stringent criteria to diagnose the disease PV. This included an initial CR51 red blood cell mass (RBCM) and I131 plasma volume. All causes of secondary PV were excluded. In an earlier cohort of 61 patients, we found that an increased RBCM, exclusion of secondary PV, and the presence of 3 of the following reliably diagnosed the phenotype of PV: serum erythropoietin level ≤ 5 mU/ml, platelet count ≥ 400 × 109/L, splenomegaly, clonal cytogenetic abnormalities, and an abnormal bone marrow histology. Results: JAK2 determinations were sequentially performed on 71 treated and untreated patients. Of these, 68 (97%) were V617F positive by allele-specific PCR analysis determined by pyrosequencing peripheral blood leukocyte DNA. We then ranked 48 patients who had not been treated with either imatinib or interferon (which affects JAK2 expression) by percent mutant allele arranged in quintiles. The highest percent mutation (80–100%) was noted in 11 patients with a phenotype of advanced disease which included massive splenomegaly (7/11 patients) and marrow fibrosis (6/11 patients). In contrast, of the group expressing 0–20% JAK2, 0/5 patients had palpable splenomegaly and 0/5 had fibrosis. The patients in the 2nd, 3rd and 4th quintiles had varying degrees of splenomegaly and fibrosis. Duration of disease could not be correlated with JAK2 V617F expression in our patients. Conclusions: We conclude that the JAK2 V617F mutation is an effective marker for diagnosing patients with PV and correlates with severity, but not duration, of disease.

No significant financial relationships to disclose.
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against unmutated or mutant Bcr-Abl-expressing human leukemia cells
Authors: Fiskus W. , Pranpat M. , Balasis M. , Atadja P. , Manley P. , Giles F. , Bhalla K.
Published: March 2020

6592

Background: AMN107 has potent in vitro and in vivo activity against the un-mutated and most mutant forms of Bcr-Abl tyrosine kinase (TK). We have previously demonstrated that in CML cells the pan-histone deacetylase inhibitor LBH589 depletes both unmutated and mutated Bcr-Abl, as well as attenuates p-AKT and Raf-1 levels. In the present studies we determined the effects of AMN107 and/or LBH589 in unmutated or mutated Bcr-Abl-expressing mouse BaF3 cells, or human CML K562 and LAMA-84 cells, as well as in primary CML cells procured from patients with imatinib mesylate (IM)-refractory CML. Methods: Cultured and primary CML cells were exposed to 20 to 100 nM AMN107 and/or LBH589 for 24 to 48 hours. Following this, the % of apoptotic cells was determined, as well as immunoblot analyses were performed to determine Bcr-Abl, p-STAT5, p-AKT, p-CrkL, Bim, Bcl-xL and p27 levels. Synergy between the apoptotic effects was determined by the median dose-effect isobologram analysis. Results: AMN107 was 20-fold more potent than IM, and was more potent in inhibiting Bcr-Abl TK activity and attenuating p-STAT5, p-AKT, Bcl-xL, and c-Myc levels in K562 and LAMA-84 cells. Co-treatment with LBH589 and AMN107 exerted synergistic apoptotic effects against human CML (but not the normal bone marrow progenitor cells), with more attenuation of p-STAT5, p-ERK1/2, c-Myc and Bcl-xL and increased p27 and Bim levels. LBH589 attenuated Bcr-Abl levels and induced apoptosis of mouse pro-B BaF3 cells containing ectopic expression of unmutated Bcr-Abl or the IM-resistant Bcr-AblT315I and Bcr-AblE255K. Treatment with LBH589 also depleted Bcr-Abl levels and induced apoptosis in IM-resistant primary human CML cells, including those with expression of Bcr-AblT315I. As compared to either agent alone, co-treatment with AMN107 and LBH589 induced more loss of cell viability of primary IM-resistant CML cells. Conclusions: These findings support in vivo testing of the combination of LBH589 and AMN107 against IM naïve or resistant CML, with the goal to eradicate IM sensitive or resistant CML.

[Table: see text]
Cytogenetic correlation with efficacy on alemtuzumab (CAM) vs chlorambucil (CHLO) as front-line therapy for patients with progressive B-cell chronic lymphocytic leukemia (BCLL)
Authors: Dmoszynska A. , Fetni R. , Wang Y. , Belkaci M. , Sirard C. , Goldberg M. , Mayer J. , Robak T. , Skotnicki A. , Hillmen P.
Published: March 2020

6601

Background: CAM307, a phase III, open-label, randomized comparative trial, enrolled 297 Rai stage I-IV BCLL patients with previously untreated, progressive disease requiring treatment. Patients were randomized to treatment with CAM (n=149) vs. CHLO (n=148) using standard dosing regimens. Methods: Cytogenetic assessment was conducted prior to the start of protocol-specified therapy. Chromosomal aberrations were detected by fluorescence in situ hybridization (FISH) using specific probes. Molecular cytogenetic analyses by FISH included deletions (del) 6q21, 6q telomere, 11q22–23, 13q14–14.3 and 17p13; trisomy bands of 8q24 and 12p11.1-q11.1. Results: A total of 271 patients have been evaluated. Chromosomal aberrations were detected in 207 patients (76%) while 64 patients (24%) exhibited normal karyotype. Cytogenetic abnormalities were evaluated by response [overall response rate (ORR) and complete response (CR)] to each therapy based upon an independent response review. The comparisons of ORR and CR between treatment arms for each mutation type were calculated using the Exact method. Conclusions: Preliminarydata demonstrate a statistically significant superior response to CAM in patients with del 13q (ORR and CR) and del 11q (ORR) as well as a statistically significant superior CR to CAM in patients with normal cytogenetics. In addition, although the sample size is small, there is a trend towards a better ORR in patients with del 17p. Further exploration of CAM response rates relative to cytogenetic abnormality is warranted.

[Table: see text]

[Table: see text]