Publications by authors named "Jorge E Cortes"

364 Publications

Efficacy and safety following bosutinib dose reduction in patients with Philadelphia chromosome‒positive leukemias.

Leuk Res 2021 Aug 21;111:106690. Epub 2021 Aug 21.

University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The recommended starting dose of bosutinib is 500 mg/day for chronic-phase (CP) or accelerated-/blast-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy. However, some patients may require dose reductions to manage the occurrences of adverse events (AEs). Bosutinib efficacy and safety were evaluated following dose reductions in a phase I/II study of Ph + patients with CP CML resistant/intolerant to imatinib or imatinib plus dasatinib and/or nilotinib, and those with accelerated-/blast-phase CML or acute lymphoblastic leukemia after at least imatinib treatment. In all, 570 patients with ≥4 years' follow-up were included in this analysis. Among 144 patients who dose-reduced to bosutinib 400 mg/day (without reduction to 300 mg/day), 22 (15 %) had complete cytogenetic response (CCyR) before and after reduction, 40 (28 %) initially achieved CCyR after reduction, and 4 (3 %) only had CCyR before reduction. Among 95 patients who dose-reduced to bosutinib 300 mg/day, 23 (24 %) had CCyR before and after reduction, 13 (14 %) initially achieved CCyR after reduction, and 3 (3 %) only had CCyR before reduction. Results were similar to matched controls who remained on 500 mg/day, indicating dose reductions had not substantially affected efficacy. The incidence of treatment-emergent AEs was lower after dose reductions, particularly for gastrointestinal events. The incidence of hematologic toxicities generally was similar before and after dose reduction. The management of AEs with bosutinib through dose reduction can lead to improved/maintained efficacy and better tolerability; still, approximately half of patients on treatment at year 4, maintained a dose of ≥500 mg/day ClinicalTrials.gov: NCT00261846.
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http://dx.doi.org/10.1016/j.leukres.2021.106690DOI Listing
August 2021

Financial assistance programs for cancer patients.

Curr Cancer Rep 2021 17;3(1):119-123. Epub 2021 Sep 17.

Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Background: The high costs of oncology care can lead to financial stress and have deleterious effects on the well-being of patients and their families. However, only a handful of financial assistance programs for cancer patients have been implemented and evaluated to date.

Recent Findings: Key features of reported programs include instrumental support through financial navigation or education for patients, and financial or charitable support for healthcare costs. Only one of the programs successfully reduced actual out-of-pocket costs for patients, though others were associated with psychosocial benefits or increased knowledge of financial resources. Four of the 5 programs evaluated to date were pilot studies with small sample sizes, and most lack control groups for comparison.

Conclusions: Additional studies are needed that include larger sample sizes and with comparison groups of cancer patients in order to determine whether the counseling and navigator programs are effective in addressing financial distress in this patient population. Of particular interest are programs designed for low-income patients and those who lack health care insurance. Financial assistance programs that implement solutions at different levels of the healthcare system (individual patients, providers, healthcare institutions) are more likely to be effective. Multi-level interventions are needed that address the systems in which patients access care, the actual costs of services and drugs, and the individual needs of patients in order to reduce financial hardship for cancer patients.
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http://dx.doi.org/10.25082/ccr.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462924PMC
September 2021

Addressing financial toxicity in oncology care.

J Hosp Manag Health Policy 2021 Sep 25;5. Epub 2021 Sep 25.

Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.

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http://dx.doi.org/10.21037/jhmhp-20-68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452270PMC
September 2021

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.

Br J Haematol 2021 Aug 2. Epub 2021 Aug 2.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34) bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.
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http://dx.doi.org/10.1111/bjh.17689DOI Listing
August 2021

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML.

J Hematol Oncol 2021 07 13;14(1):110. Epub 2021 Jul 13.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: CPX-351 (United States: Vyxeos; Europe: Vyxeos Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up.

Methods: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses.

Results: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology.

Conclusions: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete.
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http://dx.doi.org/10.1186/s13045-021-01119-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276472PMC
July 2021

CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial.

Lancet Haematol 2021 Jul;8(7):e481-e491

University of Texas MD Anderson Cancer Center, Houston, TX, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA.

Background: Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results.

Methods: This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete.

Findings: Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment.

Interpretation: After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia.

Funding: Jazz Pharmaceuticals.
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http://dx.doi.org/10.1016/S2352-3026(21)00134-4DOI Listing
July 2021

Impact of frontline treatment approach on outcomes of myeloid blast phase CML.

J Hematol Oncol 2021 06 15;14(1):94. Epub 2021 Jun 15.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0428, Houston, TX, 77030, USA.

Background: The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach.

Methods: We retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes.

Results: Response rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p < 0.05), a higher complete cytogenetic response rate (45% vs 10.7%, p < 0.001), and more patients proceeding to ASCT (32.5% vs 10.7%, p < 0.01). With a median follow-up of 6.7 years, long-term outcomes were similar between the IC + TKI and HMA + TKI groups. Combination therapy with IC/HMA + TKI was superior to therapy with TKI alone, including when analysis was limited to those treated with a 2nd/3rd-generation TKI. When using a 2nd/3rd-generation TKI, IC/HMA + TKI led to lower 5-year cumulative incidence of relapse (CIR; 44% vs 86%, p < 0.05) and superior 5-year event-free survival (EFS; 28% vs 0%, p < 0.05) and overall survival (OS; 34% vs 8%, p = 0.23) compared to TKI alone. Among patients who received IC/HMA + TKI, EFS and OS was superior for patients who received a 2nd/3rd generation TKI compared to those who received imatinib-based therapy. In a landmark analysis, 5-year OS was higher for patients who proceeded to ASCT (58% vs 22%, p = 0.12).

Conclusions: Compared to patients treated with TKI alone for CML-MBP, treatment with IC + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. Combination therapy with IC + TKI or HMA + TKI, rather than a TKI alone, should be considered the optimal treatment strategy for patients with CML-MBP.
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http://dx.doi.org/10.1186/s13045-021-01106-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204504PMC
June 2021

Health care access and utilization among adult cancer survivors: Results from the National Institutes of Health "All of Us" Research Program.

Cancer Med 2021 06 3;10(11):3646-3654. Epub 2021 May 3.

Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Background: Many cancer survivors face financial difficulties that prevent them from receiving appropriate health care. Racial/ethnic disparities in receipt of health care have been reported among cancer survivors, but recent data for important racial/ethnic subgroups of the US population are lacking.

Methods: To learn more about barriers to healthcare access faced by cancer survivors, we analyzed data from the NIH "All of Us" Research Program. Data were analyzed about demographic factors and other personal characteristics, personal medical history of cancer, healthcare utilization, and access to care.

Results: As of November 2020, a total of 5426 participants had a history of cancer (excluding skin cancer). About 88.2% were non-Hispanic White; 3.9% were Black, African American, or African; 1.3% were Asian; 4.1% were Hispanic, Latino, or Spanish; and 1.2% reported more than one race. Just over one-half had an annual income of $75,000 or greater. The majority of the participants (71.7%) were college graduates or had an advanced degree. About 47.0%% had private health insurance, 41.0% had Medicare, 6.0% had Medicaid, and the remainder had military, Veterans Affairs, other insurance, or no health insurance. Frequently cited reasons for delayed care in the past 12 months were "had to pay out of pocket for some or all of the procedures," "deductible was too high/or could not afford the deductible," "couldn't afford the copay," "couldn't get time off work," and "were nervous about seeing a health care provider."

Discussion: A minority of cancer survivors who participated in the NIH "All of Us" Program had difficulty paying for health care in the past 12 months. Of particular concern are minorities such as African American and Hispanic cancer survivors along with those who are low income.
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http://dx.doi.org/10.1002/cam4.3924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178490PMC
June 2021

Problems in living among breast cancer survivors.

Curr Cancer Rep 2021 Jun 16;3(1):101-109. Epub 2021 Apr 16.

Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Purpose: Breast cancer survivors may experience worse social, physical, and emotional function compared to the general population, although symptoms often improve over time. Data on problems in living can help to improve interventions and supportive care for breast cancer survivors. Symptoms such as fatigue, pain, difficulties with sleep, and sexual problems may have an adverse effect on the quality of life of breast cancer survivors.

Methods: We examined problems in living using data from a survey of 164 breast cancer survivors who had completed primary therapy for the disease.

Results: A total of 164 women completed the study questions (response rate 16.4%). The mean age of the women was 67 years. Among all participants, 66.7% were white, 29.5% were African-American, and the remainder were of other races. Almost all of the symptoms were more likely to be reported by participants who were < 55 years of age. Other important correlates of symptoms included non-white race, marital status, and having a household income of less than $50,000 per year.

Conclusion: The results of this study highlight the need for caregivers to emphasize screening for and discussion of symptoms, including sleep difficulties, fatigue, loss of strength, aches and pains, and muscle or joint stiffness. Of particular concern are younger survivors and those who are African American or low-income.
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http://dx.doi.org/10.25082/CCR.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086715PMC
June 2021

A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome.

Haematologica 2021 08 1;106(8):2121-2130. Epub 2021 Aug 1.

Department of Leukemia, University of Texas MD Anderson Cancer Center.

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.
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http://dx.doi.org/10.3324/haematol.2020.263392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327731PMC
August 2021

Efficacy and safety of bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia in the Asian subpopulation of the phase 3 BFORE trial.

Int J Hematol 2021 Jul 13;114(1):65-78. Epub 2021 Apr 13.

Universitätsklinikum RWTH Aachen, Aachen, Germany.

Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (n = 33 vs 34) and non-Asian (n = 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.
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http://dx.doi.org/10.1007/s12185-021-03144-4DOI Listing
July 2021

Outcome of patients with chronic myeloid leukemia in lymphoid blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with hyper-CVAD and dasatinib.

Cancer 2021 Aug 6;127(15):2641-2647. Epub 2021 Apr 6.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Dasatinib monotherapy has demonstrated modest clinical activity in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP). The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has dramatically improved with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with tyrosine kinase inhibitors (TKIs).

Methods: The authors reviewed 85 patients (23 with CML-LBP and 62 with newly diagnosed Ph-positive ALL) who received hyper-CVAD plus dasatinib.

Results: In the CML-LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML-LBP. The BCR-ABL1 transcript was p210 in 22 patients (96%) and p190 in 1 patient (4%). In the Ph-positive ALL cohort, p210 and p190 transcripts were detected in 13 patients (21%) and 48 patients (77%), respectively. Patients with CML-LBP were less likely to achieve deep molecular remission than patients with Ph-positive ALL: the major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). Survival outcomes were similar for CML-LBP and Ph-positive ALL: the 5-year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML-LBP (5-year OS rate, 88% vs 57%; P = .04). In Ph-positive ALL, the outcome was driven by deeper molecular remission: the 5-year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002).

Conclusions: The outcome of CML-LBP has improved with hyper-CVAD plus dasatinib therapy with survival comparable to that of Ph-positive ALL. Further improvement may be achieved with the use of novel TKIs and targeted agents.
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http://dx.doi.org/10.1002/cncr.33539DOI Listing
August 2021

Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial.

Ann Hematol 2021 May 19;100(5):1181-1194. Epub 2021 Mar 19.

University of Texas MD Anderson Cancer Center, Houston, TX, USA.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.
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http://dx.doi.org/10.1007/s00277-021-04465-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043884PMC
May 2021

Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.

Blood Adv 2021 03;5(6):1719-1728

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.

CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.
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http://dx.doi.org/10.1182/bloodadvances.2020003510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993093PMC
March 2021

Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.

Blood Cancer Discov 2021 Mar 6;2(2):125-134. Epub 2020 Dec 6.

The Department of Leukemia, MD Anderson Cancer Center, Houston, Texas.

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with -mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target , epigenetic modifiers, pathway, and less frequently , and . and D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment mutated patients, pretreatment cohort level variant allelic frequencies for were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in -mutated AML treated with type I versus II FLT3i.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935111PMC
March 2021

Long-term cardiac, vascular, hypertension, and effusion safety of bosutinib in patients with Philadelphia chromosome-positive leukemia resistant or intolerant to prior therapy.

Eur J Haematol 2021 Jun 21;106(6):808-820. Epub 2021 Mar 21.

Universitätsklinikum RWTH Aachen, Aachen, Germany.

Introduction: Long-term follow-up (≥4 years) demonstrated a low incidence of cardiac and vascular treatment-emergent adverse events (TEAEs) with bosutinib treatment. We evaluated cardiac, vascular, hypertension, and effusion TEAEs after ≥ 7 years of follow-up in patients with Philadelphia chromosome-positive (Ph+) leukemia.

Methods: This retrospective analysis of a phase I/II study and its ongoing extension study included data from patients with chronic phase chronic myeloid leukemia (CML) treated with bosutinib after resistance/intolerance to imatinib (CP2L) or to imatinib plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after treatment with, at a minimum, imatinib (ADV).

Results: In all, 570 patients were treated with bosutinib; median treatment duration was 11.1 months (range: 0.03-133.1). The incidence of cardiac, vascular, hypertension, and effusion-related TEAEs was 10.9%, 8.8%, 9.1%, and 13.3%, respectively. Few patients had maximum grade 3-4 TEAEs (cardiac, 3.9%; vascular, 4.0%; hypertension, 3.0%; effusion, 4.6%). Grade 5 TEAEs occurred in the cardiac (0.7%) and vascular (1.8%) clusters only. In years 5-7, fewer than 5% of patients each year had newly occurring cardiac, vascular, hypertension, or effusion TEAEs. The exposure-adjusted TEAE rates (patients with TEAEs/total patient-year) pooled across CP2L, CP3L, and ADV cohorts were as follows: cardiac, 0.044; vascular, 0.035; hypertension, 0.038; and effusion, 0.056, of which, correspondingly, 0.9%, 1.2%, 0%, and 2.1% required treatment discontinuation.

Conclusions: The incidence of cardiac, hypertension, vascular, and effusion events was low in patients with Ph+ CML resistant or intolerant to prior therapy who were treated with bosutinib.
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http://dx.doi.org/10.1111/ejh.13608DOI Listing
June 2021

Phase 2 study of lenalidomide maintenance for patients with high-risk acute myeloid leukemia in remission.

Cancer 2021 Jun 15;127(11):1894-1900. Epub 2021 Jan 15.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: New drug combinations have led to significant improvements in remission rates for patients with acute myeloid leukemia (AML). However, many patients with high-risk AML who respond to their initial treatment and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes.

Methods: In this phase 2 trial, the efficacy of lenalidomide maintenance was evaluated in patients with high-risk AML who had achieved their first or second remission after induction chemotherapy and at least 1 consolidation cycle and who were not candidates for immediate ASCT. Lenalidomide was given orally at 10 to 20 mg daily on days 1 to 28 of a 28-day cycle for up to 24 cycles.

Results: A total of 28 patients were enrolled in this study with a median age of 61 years (range, 24-87 years). The median number of cycles was 8 (range, 1-24 cycles). Ten patients (36%) completed 24 months of maintenance treatment. With a median follow-up of 22.5 months (range, 2.6-55 months), 12 patients (43%) relapsed after a median of 3 months (range, 0.7-23 months). The median duration of remission for all patients was 18.7 months (range, 0.7-55.1 months). The 2-year overall survival and relapse-free survival rates from the time of enrollment were 63% and 50%, respectively. Overall, lenalidomide was well tolerated; serious adverse events of grade 3 or 4, including rash (n = 5), thrombocytopenia (n = 4), neutropenia (n = 4), and fatigue (n = 2), were observed in 13 patients (46%).

Conclusions: Lenalidomide is a safe and feasible maintenance strategy in patients with high-risk AML who are not candidates for ASCT, and it has beneficial effects for patients with negative measurable residual disease.
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http://dx.doi.org/10.1002/cncr.33409DOI Listing
June 2021

Determination of fitness and therapeutic options in older patients with acute myeloid leukemia.

Am J Hematol 2021 04 12;96(4):493-507. Epub 2021 Jan 12.

Department of Haematology, University Hospitals Bristol, NHS Foundation Trust, Bristol, UK.

Treatment of older patients with AML remains challenging. Although age, performance status, and comorbidities are commonly employed to determine fitness for intensive treatment, several studies have demonstrated improved outcomes with treatment in older and classically unfit patients, highlighting the importance of other disease-related and patient-related factors that have prognostic value for treatment outcome in AML. However, consistent and objective assessments for fitness are lacking. Multi-parameter geriatric assessment tools offer more comprehensive evaluation, but are limited by the required resources and lack of standardization and consensus regarding prognostic value. These assessments are particularly important considering the emerging new AML therapies that represent a spectrum of intensities. Patients should therefore be evaluated holistically for fitness to receive a specific treatment, with the aim of providing individualized care, and such definitions of fitness should also consistently be applied to clinical trials. This review will examine evolving criteria for the determination of fitness among AML patients and discuss treatment options for older and/or unfit patients with AML.
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http://dx.doi.org/10.1002/ajh.26079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986910PMC
April 2021

Knowledge of prostate cancer among African American men: A systematic review.

Prostate 2021 02 23;81(3):202-213. Epub 2020 Dec 23.

Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Objective: Recent studies indicate that many African American men may not be making informed decisions about prostate cancer early detection. This is partly due to patients having limited knowledge about early detection of the disease.

Methods: The present review is based upon bibliographic searches in PubMed and CINAHL and relevant search terms. Articles (n = 235) published in English from 1993 through July 31, 2020 were identified using the following MESH search terms and Boolean algebra commands: prostate cancer and knowledge and African Americans.

Results: Forty-two articles were eligible for inclusion. The results of this literature review indicate that many African American men have inadequate knowledge of prostate cancer and prostate cancer early detection. Studies indicate that knowledge of prostate cancer is particularly low among older, less-educated, lower-income, and unmarried men, along with those who lack a regular physician or health insurance. Many African American men are unaware that they are at increased risk of prostate cancer because of their age or race.

Conclusions: Culturally appropriate educational efforts are needed to inform African- American men about the pros and cons of prostate cancer early detection and about risk factors for the disease so that they can make an informed decision about whether prostate cancer early detection is right for them. Of particular concern is the prostate cancer knowledge of low-income and less-educated men, along with those who lack health care insurance or a regular provider.
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http://dx.doi.org/10.1002/pros.24097DOI Listing
February 2021

Impact of luteinizing hormone suppression on hematopoietic recovery after intensive chemotherapy in patients with leukemia.

Haematologica 2021 04 1;106(4):1097-1105. Epub 2021 Apr 1.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

Treatment of acute leukemia with intensive chemotherapy leads to an increased risk of myelosuppression. Luteinizing hormone (LH) blockade improves hematopoietic recovery in mice after radiation or chemotherapy, through protection of the hematopoietic stem cells which express the LH receptor. We hypothesized that LH blockade improves hematopoietic recovery following intensive chemotherapy in patients with leukemia. We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received intensive chemotherapy and leuprolide given for abnormal uterine bleeding prevention or treatment. Given that leuprolide was more commonly administered in younger patients, we performed propensity score matching between the leuprolide (AML N=64; ALL N=49) and control groups (AML N=128; ALL N=98 patients). Patients with AML who received leuprolide had an additional increase of 13.8 x 109/L/year in their platelet count, and a 0.19 x 109/L/year increase in their lymphocyte count after chemotherapy compared to control (P=0.02; P=0.03 respectively). Those with ALL who received leuprolide had an additional increase of 0.37 x 109/L/year in their absolute neutrophil count (P=0.02). In AML, leuprolide was associated with higher long-term hemoglobin levels (P.
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http://dx.doi.org/10.3324/haematol.2020.256453DOI Listing
April 2021

Management of chronic myeloid leukemia during pregnancy among patients treated with a tyrosine kinase inhibitor: a single-Center experience.

Leuk Lymphoma 2021 04 7;62(4):909-917. Epub 2020 Dec 7.

Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.

Tyrosine kinase inhibitors (TKIs) are teratogenic. Chronic myeloid leukemia (CML) is increasingly identified in younger patients who wish to conceive, the management of CML during pregnancy is challenging. We reviewed 51 pregnancies involving 37 patients (30 women, 10 with >1 pregnancy and 7 men) who were either diagnosed with CML during pregnancy or receiving TKI at the time of conception. Ten women were involved in >1 pregnancies. Fifteen women were diagnosed with CML during pregnancy: 10 were treated with hydroxyurea ( = 5), interferon-alfa ( = 3), leukapheresis ( = 1), or nilotinib ( = 1). There were 14 (82%) healthy babies born on term including 2 sets of twins, 2 spontaneous miscarriages (12%), and 1 elective abortion (6%). Within 1 month of delivery or abortion, all women started TKI and achieved MR4.5 ( = 6) and MMR ( = 8) within 3-48 months. One patient, treated with interferon during pregnancy, died of blast phase within 2 months. Four of the 14 remaining women later conceived 5 other pregnancies while on TKI (3 unplanned, 2 planned). Twenty-six patients (7 men; 19 women) conceived while on TKI, with a total of 36 pregnancies. Fifteen women had 20 unplanned pregnancies while receiving TKI and discontinued immediately upon recognition of pregnancy. The median time of TKI exposure was 3 weeks (range, 2-11). Five pregnancies ended in miscarriages and 3 in elective abortion. All 7 men fathered 7 full-term healthy babies. Of 20 babies born to men and women (including one set of twins), 1 had minor abnormality. Seven women lost their responses during pregnancy but at the end of pregnancy all but 2 resumed TKI and regained responses. Seven women involved in 9 planned pregnancies discontinued TKI prior to conception for a median of 4 months (range, 1-20); 3 lost responses during pregnancy. Only 5 patients resumed therapy after delivery. Outcomes were 6 full-term healthy babies, one premature, and two miscarriages. Conception among CML patients while on TKI could be uncomplicated. While patients may lose response following treatment interruption, nearly all regain response upon resuming therapy. Therapy during pregnancy is rarely needed.
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http://dx.doi.org/10.1080/10428194.2020.1849672DOI Listing
April 2021

Optimizing management of acute leukemia in community centers and when to refer.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):123-128

Georgia Cancer Center at Augusta University, Augusta, GA.

Treatment of acute leukemia has been delivered predominantly in academic and larger leukemia treatment centers with the infrastructure and staff needed to manage patients receiving complex therapeutic regimens and supportive care. However, in recent years, several oral agents and less-myelosuppressive regimens were approved, making it possible for these patients to receive therapy in smaller community hospitals and oncology office practices. In this review, we discuss the optimum community setting, type of patient who can be treated, agents that can be applied, and an appropriate clinical circumstance in which a referral to a tertiary center should be made.
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http://dx.doi.org/10.1182/hematology.2020000096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727530PMC
December 2020

BL-8040 CXCR4 antagonist is safe and demonstrates antileukemic activity in combination with cytarabine for the treatment of relapsed/refractory acute myelogenous leukemia: An open-label safety and efficacy phase 2a study.

Cancer 2021 Apr 3;127(8):1246-1259. Epub 2020 Dec 3.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML.

Methods: Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23).

Results: BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts.

Conclusions: The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia.
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http://dx.doi.org/10.1002/cncr.33338DOI Listing
April 2021

The LEukemia Artificial Intelligence Program (LEAP) in chronic myeloid leukemia in chronic phase: A model to improve patient outcomes.

Am J Hematol 2021 02 3;96(2):241-250. Epub 2020 Dec 3.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Extreme gradient boosting methods outperform conventional machine-learning models. Here, we have developed the LEukemia Artificial intelligence Program (LEAP) with the extreme gradient boosting decision tree method for the optimal treatment recommendation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in chronic phase (CML-CP). A cohort of CML-CP patients was randomly divided into training/validation (N = 504) and test cohorts (N = 126). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum TKI treatment was suggested for each patient. The area under the curve in the test cohort was 0.81899.Backward multivariate analysis identified age at diagnosis, the degree of comorbidities, and TKI recommended therapy by the LEAP CML-CP model as independent prognostic factors for overall survival. The bootstrapping method internally validated the association of the LEAP CML-CP recommendation with overall survival as an independent prognostic for overall survival. Selecting treatment according to the LEAP CML-CP personalized recommendations, in this model, is associated with better survival probability compared to treatment with a LEAP CML-CP non-recommended therapy. This approach may pave a way of new era of personalized treatment recommendations for patients with cancer.
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http://dx.doi.org/10.1002/ajh.26047DOI Listing
February 2021

Prevention, recognition, and management of adverse events associated with gemtuzumab ozogamicin use in acute myeloid leukemia.

J Hematol Oncol 2020 10 15;13(1):137. Epub 2020 Oct 15.

Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin, is approved for the treatment of newly-diagnosed CD33 + AML in adults and children ≥ 1 month old, and relapsed or refractory CD33 + AML in adults and children ≥ 2 years old. GO treatment has been associated with an increased risk of hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), especially following hematopoietic stem cell transplantation. Other non-specific serious adverse events (SAEs) associated with GO treatment are myelosuppression, bleeding/thrombocytopenia, infusion-related reaction, and tumor lysis syndrome. This report summarizes an expert panel of physicians' recommendations for the evaluation and management of SAEs following GO, emphasizing the prevention and management of VOD/SOS.
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http://dx.doi.org/10.1186/s13045-020-00975-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559451PMC
October 2020

Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML.

J Hematol Oncol 2020 10 8;13(1):132. Epub 2020 Oct 8.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit FC4.2012, Houston, TX, 77030, USA.

Background: Second-generation FLT3-inhibitors (FLT3i) demonstrated single-agent composite CR rates (CRc) of 45-55% in patients with relapsed/refractory (R/R) FLT3-mutated AML in phase II/III trials. However, > 85% of patients treated were prior FLT3i naïve. The response rates to sequential FLT3i exposure remain poorly defined.

Methods: We retrospectively reviewed patients with FLT3-mutated AML between November 2006 and December 2019.

Results: In frontline patients treated with a FLT3i (cohort 1), the CRc rates and median overall survival (OS) with the first (n = 56), second (n = 32), and third FLT3i-based (n = 8) therapy were 77%, 31%, and 25%, and 16.7 months, 6.0 months, and 1.4 months, respectively. In patients receiving a FLT3i-based therapy for the first time in a R/R AML setting (cohort 2), the CRc rates and median OS were 45%, 21%, and 10%, and 7.9 months, 4.0 months, and 4.1 months with the first (n = 183), second (n = 89), and third/fourth (n = 29) FLT3i-based therapy, respectively. In cohort 1, CRc rates with single-agent FLT3i (n = 21) versus FLT3i-based combinations (n = 19) in second/third sequential FLT3i exposures were 19% versus 42%, respectively. In cohort 2, the CRc rates with single-agent FLT3i (n = 82) versus FLT3i-based combinations (n = 101) in first FLT3i exposure were 34% versus 53%, respectively, and those with single-agent FLT3i (n = 63) versus FLT3i-based combinations (n = 55) in second/third/fourth sequential FLT3i exposures were 13% versus 25%, respectively.

Conclusion: CRc rates drop progressively with sequential exposure to FLT3i's in FLT3-mutated AML. In all settings, CRc rates were higher with FLT3i-based combinations compared with single-agent FLT3i therapy in similar FLT3i exposure settings.
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http://dx.doi.org/10.1186/s13045-020-00964-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542942PMC
October 2020

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial.

Transplant Cell Ther 2021 02 2;27(2):153-162. Epub 2020 Oct 2.

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.

Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myelogenous leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplantation (allo-HSCT). Quizartinib, a once-daily oral, highly potent, and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 months versus 4.7 months; hazard ratio [HR], .76; 95% confidence interval [CI], .58 to .98; P = .018; composite complete remission [CRc] rate, 48% versus 27%; median duration of CRc, 2.8 months versus 1.2 months; mortality rate, .8% versus 14% by day 30, 7% versus 24% by day 60) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent on-study HSCT in QuANTUM-R at the investigator's discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median overall survival (OS) in transplant recipients versus those treated without allo-HSCT (12.2 months versus 4.4 months; HR, .315; 95% CI, .233 to .427). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT versus patients without a CRc (20.1 months versus 8.8 months; HR, .506; 95% CI, .296 to .864). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc before allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc before allo-HSCT who continued quizartinib after allo-HSCT, the median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable, and no new safety signals were identified. These results suggest that post-transplantation survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplantation and achieve durable clinical benefit. In addition, post-transplant quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.036DOI Listing
February 2021

Pregnancy outcomes in patients treated with bosutinib.

Int J Hematol Oncol 2020 May 29;9(2):IJH26. Epub 2020 May 29.

Clinic for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Universitätsklinikum RWTH Aachen, Aachen, Germany.

Aim: Preclinical studies have shown reproductive toxicity with bosutinib, but little is known about its effects during conception or pregnancy in humans.

Methods: Pregnancy cases in patients receiving bosutinib were identified from the Pfizer safety database.

Results: Thirty-three pregnancy reports were identified. Sixteen cases of maternal exposure: six live births, four abortions and six with unknown outcomes. Seventeen instances of paternal exposure: nine live births, five abortions and three with unknown outcomes.

Conclusion: Adverse effects of bosutinib exposure at conception or during pregnancy in humans cannot be excluded, particularly if therapy is not interrupted upon recognition of pregnancy. Contraceptive use is recommended for female patients receiving bosutinib, and patients should be made aware of the potential risks associated with bosutinib use during pregnancy.
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http://dx.doi.org/10.2217/ijh-2020-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510513PMC
May 2020
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