Publications by authors named "Lindsey E Roeker"

26 Publications

  • Page 1 of 1

Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation.

Blood Adv 2021 07;5(14):2879-2889

Adult Bone Marrow Transplant Service.

Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.
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http://dx.doi.org/10.1182/bloodadvances.2020003726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341347PMC
July 2021

Neutropenia in adult acute myeloid leukemia patients represents a powerful risk factor for COVID-19 related mortality.

Leuk Lymphoma 2021 08 28;62(8):1940-1948. Epub 2021 Jun 28.

Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Patients with hematological malignancies are at risk for poor outcomes when diagnosed with coronavirus disease 2019 (COVID-19). It remains unclear whether cytopenias and specific leukemia subtypes play a role in the clinical course of COVID-19 infection. Here, we report outcomes and their clinical/laboratory predictors for 65 patients with acute and chronic leukemias diagnosed with COVID-19 between 8 March 2020 and 19 May 2020 at Memorial Sloan Kettering Cancer Center in New York City. Most patients had CLL (38%) or AML (26%). A total of 14 (22%) patients required high flow nasal cannula or were intubated for mechanical ventilation and 11 patients (17%) died. A diagnosis of AML (OR 4.7, =.028), active treatment within the last 3 months (OR 5.22, =.047), neutropenia within seven days prior and up to 28 days after SARS-CoV-2 diagnosis (11.75, =.001) and ≥3 comorbidities (OR 6.55, =.019) were associated with increased odds of death.
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http://dx.doi.org/10.1080/10428194.2021.1885664DOI Listing
August 2021

Searching for a home: phosphoinositide 3-kinase inhibitors for chronic lymphocytic leukaemia in modern clinical practice.

Br J Haematol 2021 Jul 15;194(1):9-10. Epub 2021 Jun 15.

CLL Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1111/bjh.17472DOI Listing
July 2021

All in the family: back-to-back kinase inhibitors for the treatment of chronic lymphocytic Leukemia.

Haematologica 2021 Sep 1;106(9):2300-2301. Epub 2021 Sep 1.

Leukemia Service, Memorial Sloan Kettering Cancer Center.

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http://dx.doi.org/10.3324/haematol.2021.278535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409031PMC
September 2021

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

Lancet 2021 Mar;397(10277):892-901

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.

Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.

Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.

Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.

Funding: Loxo Oncology.
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http://dx.doi.org/10.1016/S0140-6736(21)00224-5DOI Listing
March 2021

Approaches for relapsed CLL after chemotherapy-free frontline regimens.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):10-17

CLL Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Novel agents, including Bruton's tyrosine kinase inhibitors (BTKi; ibrutinib, acalabrutinib), venetoclax, and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idelalisib, duvelisib), have fundamentally changed the chronic lymphocytic leukemia (CLL) treatment landscape, allowing for a chemotherapy-free paradigm for many. Randomized trials that demonstrated efficacy of these agents in the relapsed/refractory setting rarely included patients with prior novel agent exposure. Herein, we review available data, including single-arm prospective studies and retrospective cohorts, on outcomes for novel agent approaches after novel agent exposure. We examine data for subsequent treatment options in 3 specific scenarios: (1) progression of disease while receiving BTKi, (2) progression of disease after discontinuation of BTKi for intolerance, and (3) after treatment with venetoclax. Data are most robust for venetoclax-based regimens after progression on BTKi. For patients who experience progression of disease after discontinuation of BTKi for intolerance, venetoclax-based regimens and retreatment with BTKi (depending on severity of initial intolerance) are 2 data-driven options. After frontline venetoclax/obinutuzumab, subsequent treatment approaches depend on whether patients experience progression of disease during or after discontinuation of their fixed duration frontline regimen and whether venetoclax/obinutuzumab was discontinued for intolerance. After progression of disease while on venetoclax, we recommend BTKi as second-line therapy. For patients who experience progression after completion or premature discontinuation (because of intolerance) of fixed duration venetoclax/obinutuzumab, either BTKi or retreatment with venetoclax (with aggressive supportive care if prior intolerance) are reasonable considerations. Subsequent lines of therapy in these scenarios include PI3Ki and consideration of cellular therapies. Finally, clinical trial enrollment for interested patients in any line of therapy is recommended.
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http://dx.doi.org/10.1182/hematology.2020000168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727527PMC
December 2020

The Impact of Age on Survival in CLL Patients Receiving Ibrutinib as Initial Therapy.

Blood Lymphat Cancer 2020 24;10:1-5. Epub 2020 Aug 24.

Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Introduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.

Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.

Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients >65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).

Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.
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http://dx.doi.org/10.2147/BLCTT.S262592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473982PMC
August 2020

Anti-SARS-CoV-2 antibody response in patients with chronic lymphocytic leukemia.

Leukemia 2020 11 27;34(11):3047-3049. Epub 2020 Aug 27.

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1038/s41375-020-01030-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450257PMC
November 2020

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents.

Blood Adv 2020 08;4(16):3977-3989

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.
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http://dx.doi.org/10.1182/bloodadvances.2020001956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448605PMC
August 2020

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Blood 2020 09;136(10):1134-1143

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
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http://dx.doi.org/10.1182/blood.2020006965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472711PMC
September 2020

BTK Inhibitors in Cancer Patients with COVID-19: "The Winner Will be the One Who Controls That Chaos" (Napoleon Bonaparte).

Clin Cancer Res 2020 07 28;26(14):3514-3516. Epub 2020 Apr 28.

Memorial Sloan Kettering Cancer Center, New York, New York.

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367762PMC
July 2020

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

Clin Cancer Res 2020 07 20;26(14):3589-3596. Epub 2020 Mar 20.

Division of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.

Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].

Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( = 130), and 81% were idelalisib naïve ( = 263). ORR to BTKi was 84% ( = 44) in BTKi-naïve patients versus 54% ( = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3815DOI Listing
July 2020

Hypertension in Patients Treated With Ibrutinib for Chronic Lymphocytic Leukemia.

JAMA Netw Open 2019 12 2;2(12):e1916326. Epub 2019 Dec 2.

Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1001/jamanetworkopen.2019.16326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902749PMC
December 2019

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Br J Haematol 2020 03 4;188(6):918-923. Epub 2019 Nov 4.

Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
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http://dx.doi.org/10.1111/bjh.16271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528953PMC
March 2020

Incidence, Predictors, and Outcomes of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 03 31;26(3):529-539. Epub 2019 Oct 31.

Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer, Institute, Harvard Medical School, Boston, Massachusetts. Electronic address:

fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P = .006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P = .0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P = .06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P = .002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P < .001) or other (HR, 32; 95% CI, 3.9 to 257; P = .001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.024DOI Listing
March 2020

A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL.

Blood Adv 2019 05;3(10):1568-1573

Swedish Cancer Center, Seattle, WA.

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; = .7) and HR 1.2 (95% CI, 0.6-2.3; = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings.
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http://dx.doi.org/10.1182/bloodadvances.2019000180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538868PMC
May 2019

Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice.

Clin Cancer Res 2019 07 19;25(14):4264-4270. Epub 2019 Apr 19.

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.

Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.

Results: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated , 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.

Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020996PMC
July 2019

Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial.

Am J Hematol 2018 11 26;93(11):1394-1401. Epub 2018 Sep 26.

Cardinal Health, Dublin, Ohio.

Ibrutinib demonstrated superior response rates and survival for treatment-naïve chronic lymphocytic leukemia (CLL) patients in a pivotal study that excluded patients younger than 65 (<65) and/or with chromosome 17p13 deletion (del[17p13]). We examined outcomes and toxicities of CLL patients who would have been excluded from the pivotal study, specifically <65 and/or those with del[17p13]. This multicenter, retrospective cohort study examined CLL patients treated with front-line ibrutinib at 20 community and academic centers, categorizing them based on key inclusion criteria for the RESONATE-2 trial: <65 vs ≥65 and present vs absent del[17p13]. Of 391 included patients, 57% would have been excluded from the pivotal study. Forty-one percent of our cohort was <65, and 30% had del(17p13). Patients <65 were more likely to start 420 mg of ibrutinib daily; those who started at reduced doses had inferior PFS. The most common adverse events were arthralgias, fatigue, rash, bruising, and diarrhea. Twenty-four percent discontinued ibrutinib at 13.8 months median follow-up; toxicity was the most common reason for discontinuation, though progression and/or transformation accounted for a larger proportion of discontinuations in <65 and those with del(17p13). Response rates were similar for <65 and those with del(17p13). However, patients with del(17p13) had inferior PFS and OS. Ibrutinib in the front-line setting has extended beyond the population in which it was initially studied and approved. This study highlights and compares important differences in ibrutinib dosing, treatment interruptions, toxicities, reasons for discontinuation, and survival outcomes in two important patient populations not studied in RESONATE-2.
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http://dx.doi.org/10.1002/ajh.25261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552812PMC
November 2018

Early Clinical Predictors of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Myeloablative Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 01 3;25(1):137-144. Epub 2018 Aug 3.

Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is a serious complication of hematopoietic stem cell transplantation (HSCT) with mortality in its severe form exceeding 80%. Although the incidence of VOD/SOS has fallen with contemporary transplantation practices, the increasing use of inotuzumab, the return of gemtuzumab, and the popularity of pharmacokinetic-guided high-dose busulfan may impact incidence. Early intervention with defibrotide improves survival, but prompt diagnosis can be difficult. We aimed to identify clinical parameters that could aid in early detection of VOD/SOS in a large, retrospective, cohort study. Of the 1823 adult patients who underwent myeloablative HSCT between 1996 and 2015 in our center, 205 (11%) developed VOD/SOS, with a median onset of day +14. We compared parameters in the 7 days preceding VOD/SOS onset for cases to 447 randomly selected control subjects in an analogous time frame to determine those with predictive value. Between 7 days before and the day of diagnosis, VOD/SOS patients had higher serum creatinine levels and were more likely to develop acute kidney injury (61% versus 33%, P < .0001), more commonly experienced refractoriness to platelet transfusion (48% versus 24%, P < .0001), and had higher trough serum tacrolimus levels (7 days before VOD/SOS onset: median 8.8 versus 7.3, P = .0002; day of onset: median 9.3 versus 7.2, P < .0001) compared with control subjects. Acute renal dysfunction, platelet refractoriness, and elevated or abnormal tacrolimus levels are dynamic clinical markers that should alert clinicians to the development of VOD/SOS before the presence of classical diagnostic criteria. Using these clinical features to recognize VOD/SOS earlier in its clinical course could promote earlier treatment and lead to improved outcomes of this potentially serious complication.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.039DOI Listing
January 2019

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Haematologica 2018 09 7;103(9):1511-1517. Epub 2018 Jun 7.

CLL Program, Leukemia Service, Division of Hematologic Oncology, Department of Internal Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated , 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.
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http://dx.doi.org/10.3324/haematol.2018.193615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119152PMC
September 2018

Outcomes of Patients With Familial Transthyretin Amyloidosis After Liver Transplantation.

Prog Transplant 2017 09 4;27(3):246-250. Epub 2017 Jul 4.

7 Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Background: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis.

Research Question: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation.

Design: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed.

Results: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase.

Discussion: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.
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http://dx.doi.org/10.1177/1526924817715463DOI Listing
September 2017

Cervical cancer screening in Ghana, west Africa: prevalence of abnormal cytology and challenges for expanding screening.

Int J Gynecol Pathol 2014 Mar;33(2):197-202

Mayo Clinic College of Medicine (K.S.H., R.J.M., L.E.R., N.P.N., M.J.B., A.C., L.R., K.M.) Rochester, Minnesota Departments of Pathology (S.Q., O.O.-A., E.A.) Obstetrics/Gynecology (F.A.), Komfo Anokye Teaching Hospital Kwame Nkrumah University of Science and Technology (F.A., D.A.), Kumasi, Ghana.

Aims were to assess the prevalence of Papanicolaou (Pap) abnormalities found with cervical cancer screening in Agogo and Nkawie, communities in the Ashanti region of Ghana, and compare the correlation between Pap readings performed at the Komfo Anokye Teaching Hospital in Kumasi, Ghana, and at the Mayo Clinic cytology laboratory in Rochester, MN. Demographic data was collected and Pap tests were performed on women recruited for screening in the communities of Agogo (n=119) and Nkawie (n=255). The Pap tests were assessed by pathology laboratory staff at Komfo Anokye Teaching Hospital and Mayo Clinic. There was a significant difference in prevalence of abnormal cytology between the sites with a rate of 12.6% in Agogo and 3.5% in Nkawie (P=0.016). Demographic differences were noted in education level (P<0.001), occupation (P<0.001), religion (P=0.002), and marital status (P<0.001). The Cohen correlation coefficient between the two pathology departments interpreting samples was 0.185, which indicates a significant degree of discordance (P<0.001). Currently Ghana does not have a national cervical cancer screening program. Identifying higher risk communities and patients as a priority for screening may be useful with limited resources. Accurate identification of Pap abnormalities is necessary to implement an effective screening program.
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http://dx.doi.org/10.1097/PGP.0b013e318298a9e6DOI Listing
March 2014

Cyclic bicytopenia in a patient with shapiro syndrome.

Case Rep Hematol 2013 25;2013:231713. Epub 2013 Sep 25.

Mayo Medical School, Mayo Clinic, Rochester, USA.

Shapiro syndrome and periodic hypothermia have been reported approximately fifty times in the literature. Shapiro syndrome is defined as the constellation of periodic hypothermia and hyperhidrosis along with agenesis of the corpus callosum by Shapiro et al. in 1969. Periodic hypothermia is a more broad diagnosis with a number of proposed mechanisms; it occurs in patients without structural brain abnormalities. Hematologic abnormalities beyond iron-deficiency anemia have not been documented in any of the reported cases of Shapiro syndrome or periodic hypothermia. Though accidental and therapeutic hypothermia have been associated with thrombocytopenia, this is, to our knowledge, the first reported case of periodic intrinsic hypothermia causing bicytopenia. In this report, we present the case of a patient with Shapiro syndrome who experienced cyclic bicytopenia mirroring hypothermic episodes. We address the differential diagnosis of bicytopenia, review the mechanisms proposed for cytopenias related to hypothermia, and propose possible mechanisms for the finding in this case.
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http://dx.doi.org/10.1155/2013/231713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800621PMC
November 2013

Imatinib-associated melanosis of the palate.

Am J Hematol 2014 May 3;89(5):564. Epub 2014 Mar 3.

Mayo Medical School, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1002/ajh.23589DOI Listing
May 2014
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