Day: 01/28/2023

Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer

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Background

Chemotherapy plus anti-HER2 therapy is the mainstay systemic treatment for patients with HER2-positive early breast cancer.1–3 Despite additional anti-HER2 targeted therapies entering clinical practice, trastuzumab remains the standard of care for all patients.1–3 In patients with node-negative small tumors, chemotherapy burden can be de-escalated by administering weekly paclitaxel for 3 months and concurrent trastuzumab for 1 year.4

Considering its major negative impact on patients’ quality of life, developing treatment-induced premature ovarian insufficiency (POI) is a crucial age-related issue to be discussed with all premenopausal women.5,6 Currently, treatment-induced POI is mostly defined based on amenorrhea after anticancer therapies.7 However, irrespective of menstrual cycle perturbation during treatment and restoration after its completion, anticancer agents may cause direct damage to the primordial follicle pool (ie, the ovarian reserve) that can lead to fertility-related problems and early menopause.5,6 Therefore, the current definition of treatment-induced POI is considered suboptimal and other parameters, including ovarian reserve markers and posttreatment pregnancies, may more properly reflect the impact of anticancer therapies on women’s ovarian reserve and fertility potential.5,6 Produced by granulosa cells of growing follicles, antimüllerian hormone (AMH) is considered an established biomarker of ovarian reserve widely used in women undergoing in vitro fertilization procedures.8,9 It is more sensitive than other hormonal markers and has the advantage of showing little variation during regular menses.8–10 In patients with cancer, AMH measurement during systemic therapies is considered a promising biomarker for quantifying treatment-induced gonadotoxicity, thus aiding in the diagnosis and prediction of POI.11

With all newly diagnosed premenopausal women, discussing gonadotoxicity risk is the starting point for proper oncofertility counseling.5,6,12,13 However, although the risk and mechanisms of gonadotoxicity with anthracycline/cyclophosphamide-based chemotherapy and their impact on patients’ ovarian reserve are well established,14–16 the gonadal effect of anti-HER2 targeted agents remains largely unknown, and limited conflicting evidence exists for taxanes.5,6

In the NeoALTTO (BIG 1-06) trial (ClinicalTrials.gov identifier: NCT00553358), patients with HER2-positive early breast cancer received neoadjuvant treatment with anti-HER2 therapy alone (trastuzumab and/or lapatinib) for 2 cycles (6 weeks total) and then together with weekly paclitaxel for 12 cycles before surgery.17 Considering that AMH level can be an early indicator of gonadotoxicity, with a significant decline in its values within 2 weeks after treatment initiation,18,19 the NeoALTTO trial represented a unique setting to explore for the first time the acute gonadal impact of anti-HER2 therapy alone and in combination with weekly paclitaxel in patients not previously exposed to anthracycline/cyclophosphamide-based chemotherapy.

Patients and Methods

Study Design and Participants

Details of the NeoALTTO trial design were previously reported.17 Briefly, NeoALTTO was a multicenter, open-label, randomized phase III neoadjuvant study in female patients with HER2-positive early breast cancer. Eligible patients were randomly assigned to receive anti-HER2 therapy alone (lapatinib or trastuzumab or their combination) for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks before surgery. After surgery, 3 cycles of 5-fluorouracil + epirubicin + cyclophosphamide was administered followed by 34 additional weeks of the same anti-HER2 therapy received in the neoadjuvant phase.

The present analysis included only female patients aged ≤45 years and with known premenopausal status at randomization, with available serum samples at baseline and at least at 1 additional time point during the neoadjuvant treatment phase.

The NeoALTTO trial was approved by the independent review boards of participating centers, and all included patients provided written informed consent before study entry. The TransALTTO and NeoALTTO Steering Committees approved the present analysis.

Study Procedures

As per the NeoALTTO trial design, all included patients underwent prospective serum sample collection at predefined specific time points. For patients eligible for the present project, serum samples at the following time points were requested for AMH testing: screening/baseline (ie, before administration of any anticancer treatment), week 2 (ie, the “biological window” of anti-HER2 therapy alone), and surgery (ie, the end of 12 cycles of weekly paclitaxel + anti-HER2 therapy and before starting adjuvant chemotherapy).

All frozen serum samples were transferred to the Biobank of Gynecology of Erasmus at the Research Laboratory on Human Reproduction, Université Libre de Bruxelles (ULB) in Brussels, Belgium. Central AMH testing was performed with the Roche Elecsys AMH Plus assay according to manufacturer instructions. The limit of detection was 0.01 ng/mL (0.07 pmol/L).

Study Objectives and Variables of Interest

The primary objective of this analysis was to assess the acute gonadotoxicity of anti-HER2 agents alone or in combination with taxane-only chemotherapy using serum AMH levels as a measure of treatment impact on women’s ovarian reserve.

As secondary objectives, we investigated the impact of the different anti-HER2 agents and of patient age and baseline ovarian reserve (ie, AMH levels) on treatment-induced acute gonadotoxicity.

Statistical Analysis

Sample size calculations and statistical assumptions for the primary endpoint of the NeoALTTO trial were previously described.17 The present analyses focusing on treatment-induced acute gonadotoxicity measured by AMH levels were not preplanned in the protocol and the power of the statistical analyses was not prespecified. Given the highly skewed distribution of AMH levels and the descriptive intent of this analysis, data were summarized using a nonparametric statistical approach. Medians and interquartile ranges (IQRs) were used to summarize AMH levels at each time point. Scatter plots and box plots were used to present AMH dynamics during treatment.

The cumulative variation between AMH levels after 2 weeks and before surgery with respect to AMH levels at baseline was calculated according to the following formula19:

ΔBX=(AMHX−AMHB)/(AMHB−0.0098)*100,

where AMHB is at baseline, AMHX is at each of the 2 other time points, and 0.0098 is the lowest AMH observed value. The difference between the 2 ΔBX was calculated.

The analyses were first conducted in the overall study population, irrespective of treatment arm. Then, the same analyses were conducted by treatment arm (lapatinib vs trastuzumab vs trastuzumab + lapatinib), by patient age (as categorical variable: <35 vs 35–40 vs 41–45 years) and by pretreatment AMH levels (as categorical variable: first vs second vs third tertile). Kruskal-Wallis tests were used for group comparison at each time point. To compare AMH at 2 different time points, the Wilcoxon matched-pairs signed rank test was applied. The Skillings-Mack test was used to perform an overall comparison between AMH values at each time point.20

The impact of age and pretreatment AMH levels as continuous variables on changes in AMH values during therapy was assessed via the Spearman correlation coefficient, and the Lowess method was applied to visualize the trends.21

Statistical analysis was conducted (M. Bruzzone, M. Ceppi) using Stata, Version 13.1 (StataCorp LP). Statistical tests were 2-sided, and P values <.05 were considered statistically significant.

Results

Of 455 women randomized in the NeoALTTO trial between January 2008 and May 2010, 139 were premenopausal and aged ≤45 years at randomization. Serum samples were not available or could not be tested for AMH level at baseline in 9 patients, resulting in a final cohort of 130 patients (Figure 1).

Figure 1.

Figure 1.

Study flow of participants.

Abbreviation: AMH, antimüllerian hormone.

aTesting for AMH, with prespecified time points of screening/baseline (ie, before administration of any anticancer treatment), week 2 (ie, the “biological window” of anti-HER2 therapy alone), and surgery (ie, the end of 12 cycles of weekly paclitaxel + anti-HER2 therapy and before starting adjuvant chemotherapy).

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

Median age was 38 years (IQR, 33–42 years), and 86 (66.2%) patients were aged ≤40 years (Table 1). A total of 41 (31.5%), 45 (34.6%), and 44 (33.9%) patients were randomized to the trastuzumab, lapatinib, or trastuzumab + lapatinib arms, respectively.

Table 1.

Patient and Tumor Characteristics

Table 1.

AMH values differed significantly at the 3 time points (P<.001; Figure 2A). At screening/baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56–2.62 ng/mL). After 2 weeks of anti-HER2 treatment alone, a small reduction in AMH levels was observed with a median value of 1.10 ng/mL (IQR, 0.45–2.09 ng/mL; P<.001). At surgery, after paclitaxel and anti-HER2 therapy, a major significant decline in AMH levels was observed with a median value of 0.01 ng/mL (IQR, 0.01–0.03 ng/mL; P<.001).

Figure 2.

Figure 2.

AMH dynamic in the whole study cohort. (A) Evolution of serum AMH levels at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviations: AMH, antimüllerian hormone; H0, null hypothesis.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

Overall, the percentages of AMH change at week 2 and at surgery differed significantly with respect to baseline (P<.001; Figure 2B). Compared with baseline values, the median cumulative decrease in AMH levels was −12.5% (IQR, −37.6% to 12.4%) at week 2 and −99.9% (IQR −100.0% to −98.7%) at surgery. Compared with week 2 values, the median cumulative decrease in AMH levels at surgery was −80.7% (IQR, −109.5% to −54.8%).

There was no significant difference between treatment arms (trastuzumab vs lapatinib vs trastuzumab + lapatinib) either in the degree of reduction in AMH levels (Figure 3A, supplemental eTable 1, available with this article at JNCCN.org) or in the degree of cumulative decrease in AMH levels (Figure 3B, supplemental eTable 2) at the different time points.

Figure 3.

Figure 3.

AMH dynamic by treatment arm (lapatinib, lapatinib + trastuzumab, and trastuzumab). (A) Evolution of serum AMH levels at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviations: AMH, antimüllerian hormone; Lap, lapatinib; Tras, trastuzumab.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

At screening/baseline, median AMH levels were 2.76 ng/mL (IQR, 1.40–4.07 ng/mL), 1.33 ng/mL (IQR, 0.95–2.25 ng/mL), and 0.52 ng/mL (IQR, 0.12–1.01 ng/mL) in patients aged <35, 35–40, and 41–45 years, respectively. AMH levels remained significantly different between age groups at all time points (P<.001; Figure 4A, supplemental eTable 3 and eFigure 1). A significant negative correlation was observed between age and AMH levels at baseline (r = −0.609; P<.001; supplemental eFigure 2A), at week 2 (r = −0.617; P<.001; supplemental eFigure 2B), and at surgery (r = −0.500; P<.001; supplemental eFigure 2C).

Figure 4.

Figure 4.

AMH dynamic by age group (ages <35, 35–40, and 41–45 years). (A) Evolution of serum AMH level at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviation: AMH, antimüllerian hormone.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

The difference between age groups in the degree of reduction in AMH levels (P<.001; Figure 4B, supplemental eTable 4) and the negative correlation between age and degree of decrease in AMH levels (r = −0.326; P<.001; supplemental eFigure 3A–C) were significant only at surgery compared with baseline.

Based on pretreatment AMH levels, the cutoffs to distinguish between the 3 tertiles were <0.74, 0.74 to 1.98, and >1.98 ng/mL. AMH levels remained significantly different between AMH tertile groups at all time points (P<.001; Figure 5A, supplemental eTable 5). A significant positive correlation was observed between AMH tertile groups and AMH levels at week 2 (r = 0.91; P<.001; supplemental eFigure 4A) and at surgery (r = 0.54; P<.001; supplemental eFigure 4B).

Figure 5.

Figure 5.

AMH dynamic by pretreatment AMH tertile groups (1st: <0.74; 2nd: 0.74–1.98; 3rd: >1.98). (A) Evolution of serum AMH level at the 3 time points (baseline, week 2, and at surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviations: AMH, antimüllerian hormone; T, tertile.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

The difference between AMH tertile groups in the degree of reduction in AMH levels (P<.001; Figure 5B, supplemental eTable 6) and the positive correlation between AMH tertile groups and the degree of decrease in AMH levels (r = 0.297; P=.002; supplemental eFigure 5A–C) were significant only at surgery compared with baseline.

After repeating the main analyses by including only patients with all 3 samples (screening/baseline, week 2, and surgery) available for AMH testing (n=107), we observed consistent results (supplemental eTables 7–15).

A total of 7 patients had a pregnancy after treatment completion; all were aged <35 years at randomization. Median AMH levels were 3.22 ng/mL (IQR, 1.99–4.61 ng/mL) at screening/baseline, 2.74 ng/mL (IQR, 1.81–3.69 ng/mL) after 2 weeks of anti-HER2 treatment alone, and 0.04 ng/mL (IQR, 0.03–0.04 ng/mL) at surgery after paclitaxel and anti-HER2 therapy.

In patients without subsequent pregnancy and aged <35 years (n=35), median AMH levels were 2.55 ng/mL (IQR, 1.34–4.02 ng/mL) at baseline, 2.15 ng/mL (IQR, 1.24–3.43 ng/mL) at week 2, and 0.04 ng/mL (IQR, 0.01–0.08 ng/mL) at surgery. There were no significant differences in AMH levels at baseline (P=.16), week 2 (P=.463), or surgery (P=.610) in patients with or without subsequent pregnancy.

Discussion

This biomarker analysis of the NeoALTTO trial explored the short-term impact of anti-HER2 therapy alone and then combined with weekly paclitaxel on ovarian reserve measured by AMH levels in premenopausal women with HER2-positive early breast cancer not previously exposed to anthracycline/cyclophosphamide-based chemotherapy. We observed a small reduction in AMH levels during 2 weeks of anti-HER2 treatment alone and then a profound decline to almost undetectable levels in most patients after its combination with weekly paclitaxel. Although type of anti-HER2 targeted agent did not demonstrate any influence, age and pretreatment ovarian reserve had a major impact on the acute risk of treatment-induced gonadotoxicity. This analysis provides novel important information to share with premenopausal patients with breast cancer to improve their oncofertility counseling.

Defining the gonadotoxicity of targeted agents is considered an important unmet clinical need.5,6,22 In patients receiving mostly anthracycline/cyclophosphamide-based chemotherapy, adding trastuzumab to cytotoxic therapy did not seem to increase posttreatment amenorrhea risk,23,24 and no differences were observed when using trastuzumab and/or lapatinib.25 Low rates of posttreatment amenorrhea were observed in premenopausal women receiving trastuzumab and weekly paclitaxel.26 Although these studies suggested no apparent negative gonadotoxic impact of anti-HER2 therapy, all patients received prior or concurrent chemotherapy, and amenorrhea was used as a marker of gonadotoxicity. Hence, the actual impact of anti-HER2 targeted therapy on patients’ ovarian reserve remains undefined.5,6,22 Our data suggest that there could be a possible negative short-term gonadal effect of these agents. Considering that the EGFR signaling pathway has an important role in ovarian function,27 HER2 blockade could theoretically impact the rate of ovarian follicle activation and subsequent follicle growth.27,28 Most serum AMH derives from small antral follicles29; these findings indicate an effect of anti-HER2 blockade on the growing follicles. Due to the short treatment period of 2 weeks and the lack of a recovery period before starting chemotherapy, these data cannot inform on whether anti-HER2 blockade has effects on ovarian primordial follicles, which would translate into a long-term impact on ovarian function. Although significant, the observed reduction in AMH levels after 2 weeks of anti-HER2 treatment alone was small, in marked contrast to what has been observed with chemotherapy over this short 2-week window.18,19 No further reduction in AMH levels was observed with dual anti-HER2 blockade compared with trastuzumab and lapatinib given as single agents. Although it is possible that greater AMH declines would be seen with longer use of anti-HER2 therapy without chemotherapy, it is also plausible that any impact of anti-HER2 therapy on ovarian function may be transient and reversible (similar to the impact on cardiac ejection fraction). Thus, the gonadal effect of these anti-HER2 therapies may have limited clinical impact compared with the subsequent ovarian damage induced by chemotherapy. Considering that other anti-HER2 agents, including antibody–drug conjugates, have entered clinical practice or are in late stages of development in patients with HER2-positive early breast cancer, further efforts in this field are eagerly awaited.22,30

The risk of treatment-induced POI with cyclophosphamide and anthracyclines is well established.5,6 In most patients receiving these agents, AMH levels decline to undetectable values during treatment, with only partial and minimal recovery after therapy completion.19 More limited evidence exists to counsel women receiving taxane-based chemotherapy.14 Adding a taxane to anthracycline/cyclophosphamide-based chemotherapy is associated with a further increased risk of treatment-induced amenorrhea25,31 and a more profound short-term reduction in AMH levels,32 without apparent differences between docetaxel and paclitaxel.25 Compared with sequential regimens, similar rates of treatment-induced amenorrhea are expected with the use of docetaxel combined with cyclophosphamide or carboplatin (+ anti-HER2 therapy).25,33

Considering that weekly paclitaxel + trastuzumab is currently widely used in the clinic,4 the possibility of studying its gonadal impact without prior exposure to or coadministration of cyclophosphamide or anthracyclines is invaluable. In the APT trial, the observed rate of treatment-induced amenorrhea (28%) seemed to be lower than historically expected with cyclophosphamide/anthracycline-based chemotherapy regimens.26 Nevertheless, our analysis suggests that weekly paclitaxel alone has a major acute negative impact on women’s ovarian reserve, leading to a profound decline in AMH levels similar to what was expected with other known gonadotoxic chemotherapy agents. However, it is also possible that concurrent anti-HER2 therapy also contributed to this gonadotoxic effect. A future analysis within the Decrescendo trial (ClinicalTrials.gov identifier: NCT04675827) investigating the potential subsequent recovery of women’s ovarian reserve in the long term is awaited to further characterize the gonadotoxicity of single-agent taxane plus anti-HER2 therapy.

Age and baseline ovarian reserve measured by AMH levels are the most important patient-related factors influencing gonadotoxicity risk.5,6,11 These factors were confirmed in our analysis, showing a clear trend for a more profound reduction in AMH levels in older patients and those with the lowest baseline values. Nevertheless, all women (including the youngest and those with the highest baseline values) had a major acute reduction in AMH levels to very low/undetectable values after treatment using weekly paclitaxel and anti-HER2 agents. Therefore, although most young women with breast cancer, and particularly those aged <35 years and with optimal baseline ovarian reserve, are likely to retain ovarian function after chemotherapy completion and to conceive spontaneously,34,35 such treatments do cause ovarian damage. Hence, all women with breast cancer receiving systemic anticancer treatments should be considered at risk for treatment-induced gonadotoxicity and receive oncofertility counseling, including the possibility of undergoing fertility preservation strategies.5,6

In assisted reproductive technology, AMH is an excellent biomarker for predicting oocyte yield after ovarian stimulation.8,9 However, AMH is a poor predictor of pregnancy, because pregnancy can also occur in women with low/undetectable AMH levels.36 In our analysis, although information on AMH levels at conception or pregnancy attempts was not available, no apparent differences were observed in post-paclitaxel and anti-HER2 treatment values between patients with or without a subsequent pregnancy. Although AMH represents a biomarker of treatment-induced ovarian damage,11 it should not be regarded as a fertility test or a measure of reproductive potential, particularly during or soon after chemotherapy.

Among limitations, this analysis was not preplanned in the study protocol. There were no available serum samples after surgery, and therefore the potential recovery of AMH levels after treatment completion could not be assessed. No information on menstrual function after treatment was registered. Nevertheless, all samples were prospectively collected during study conduction at precise time points and their storage followed strict standard operating procedures. An automated and sensitive AMH assay, which offers improved precision compared with previously available assays, was used to centrally test all samples. The uniqueness of this analysis is represented by the possibility to study the gonadal impact of both anti-HER2 agents alone and weekly paclitaxel without the prior confounding effect of anthracycline/cyclophosphamide-based chemotherapy. Although data on previous gynecologic history, fertility treatments, or reproductive outcomes were not available, data on posttreatment pregnancies were collected, allowing us to obtain additional information on the impact of such therapies on patients’ fertility.

Conclusions

This NeoALTTO biomarker analysis in premenopausal patients with HER2-positive early breast cancer not previously exposed to anthracycline/cyclophosphamide-based chemotherapy provides evidence on the potential acute impact of anti-HER2 therapy alone (trastuzumab and/or lapatinib) and together with weekly paclitaxel on ovarian reserve measured by AMH levels. These data add to the body of knowledge in the oncofertility field that weekly paclitaxel + anti-HER2 therapy may cause gonadal damage, thus highlighting the importance of oncofertility counseling among premenopausal women receiving this regimen. Age and pretreatment ovarian reserve remain key determinants of treatment-induced gonadotoxicity risk.

Source: jnccn.org

FDA Approves Zanubrutinib in Treatment of CLL or SLL

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U.S. Food and Drug Administration (FDA) approved the kinase inhibitor zanubrutinib (Brukinsa) in the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Efficacy in patients with treatment-naive CLL or SLL was evaluated in the SEQUOIA trial (ClinicalTrials.gov identifier NCT03336333). In the randomized cohort of the SEQUOIA trial, including patients without 17p deletion, a total of 479 patients were randomly assigned 1:1 to receive either zanubrutinib until disease progression or unacceptable toxicity or bendamustine plus rituximab (BR) for six cycles. The median progression-free survival was not reached in the zanubrutinib arm and was 33.7 months in the BR arm (hazard ratio = 0.42, 95% confidence interval [CI] = 0.28–0.63; P < .0001). Estimated median follow-up for progression-free survival was 25.0 months.

In a separate nonrandomized cohort of SEQUOIA, zanubrutinib was evaluated in 110 patients with previously untreated CLL or SLL with 17p deletion. The overall response rate per independent review committee was 88% (95% CI = 81%–94%). The median duration of response was not reached after a median follow-up of 25.1 months.

Efficacy in patients with relapsed or refractory CLL or SLL was evaluated in the ALPINE trial (NCT03734016). A total of 652 patients were randomly assigned 1:1 to receive either zanubrutinib or ibrutinib. The median number of prior lines of therapy was one (range, 1–8). The overall response rate was 80% (95% CI = 76%–85%) with zanubrutinib and 73% (95% CI = 68%–78%) with ibrutinib (response rate ratio, 1.10, 95% CI = 1.01–1.20; P = .0264). The median duration of response was not reached in either arm, after a median follow-up of 14.1 months.

Across clinical trials of zanubrutinib, the most common adverse reactions (≥ 30%) were neutrophil count decreased (42%), upper respiratory tract infection (39%), platelet count decreased (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, including non-skin carcinomas, developed in 13% of patients. Atrial fibrillation or flutter was reported in 3.7% of patients, and grade 3 or higher ventricular arrhythmia was noted in 0.2% of patients.

The recommended zanubrutinib dosage is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

Ibrutinib Plus Bendamustine and Rituximab

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SHINE Regimen for Older Patients With Mantle Cell Lymphoma

Mantle cell lymphoma is a rare subtype of non-Hodgkin lymphoma that accounts for approximately 4,000 cases a year, with a median age at diagnosis in the mid to late 60s. The standard approach for newly diagnosed mantle cell lymphoma has been the use of intensive first-line chemoimmunotherapy regimens followed by high-dose therapy and autologous stem cell rescue (associated with a median progression-free survival of more than 8 years). Progress over the past few years has resulted in the development of better treatment options in the second-line setting, as well. In older patients, however, common comorbidities often prevent the use of intensive therapies, and the standard of care has been the use of less intensive regimens (eg, bendamustine plus rituximab)1 followed by maintenance rituximab. There are now six drugs approved in the United States in the relapsed or refractory setting, yielding a high overall response rate and duration of response, even in patients whose disease is resistant to chemoimmunotherapy.

“Given the game-changing paradigm that Bruton’s tyrosine kinase [BTK] inhibitors [ibrutinib was the first approved agent in the class] represent in relapsed or refractory mantle cell lymphoma, it was logical to bring this approach into earlier lines of therapy,” said Andre Henri Goy, MD, Chairman and Chief Physician Officer, and Lymphoma Division Chief, John Theurer Cancer Center at Hackensack University Medical Center, in New Jersey.

Ibrutinib has notable single-agent efficacy in later lines of treatment for mantle cell lymphoma, and the results of the SHINE trial demonstrated the efficacy of ibrutinib in the first-line setting when used in combination with bendamustine plus rituximab.  [Editor’s Note: The SHINE regimen is not currently listed as an option for induction therapy in the NCCN Guidelines for B-cell lymphoma.]

The median age of patients on the SHINE trial was 71 years. Rituximab was also given as maintenance therapy for 2 years in patients with a complete or partial response.

Findings presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine showed a 50% increase in progression-free survival among patients (> 65 years) who received the triplet regimen of ibrutinib plus bendamustine/rituximab versus bendamustine plus rituximab alone.2,3 Patients who were randomly assigned to receive ibrutinib plus bendamustine/rituximab had a median progression-free survival of 80.6 months versus 52.9 months for bendamustine plus rituximab alone. The complete response rate was 65.5% in the ibrutinib-containing arm versus 57.6% in the placebo arm (P = .0567).

Testing for Genetic Abnormalities

According to Dr. Goy, the more than 2-year difference in progression-free survival and the increase in the time to next treatment are “highly significant in this population” (median age, 71 years), “but there was no difference in overall survival at this point. It is also a bit surprising to see no difference in complete response rate, given the high activity of ibrutinib in the relapsed/refractory setting, although measurable residual disease (MRD)-negative status by flow cytometry seemed higher in the ibrutinib plus bendamustine/rituximab arm compared with bendamustine/rituximab alone (62% versus 51%),” Dr. Goy told JNCCN 360.

“For newly diagnosed, older patients who are ineligible for transplant, the combination of bendamustine/rituximab and ibrutinib offers a longer mileage than bendamustine/rituximab alone,” he continued. Nevertheless, “one also needs to consider the added toxicity of ibrutinib, and the fact that high-risk patients showed less benefit with the combination.”

For newly diagnosed, older patients who are ineligible for transplant, the combination of bendamustine/rituximab and ibrutinib offers a longer mileage than bendamustine/rituximab alone.

According to Dr. Goy, genetic testing using next-generation sequencing is now increasingly available and may help identify patients who do poorly with standard approaches, particularly patients with p53 mutations, for example.

“Even with high-dose therapy, regardless of intensity, the median survival for patients with p53 mutations is dramatically shorter at approximately 18 months,” said Dr. Goy. “For those patients with p53 abnormalities, exposure to cytotoxic agents leads to earlier chemoresistance and impaired outcomes.”

On the other hand, Dr. Goy explained, patients with a complex karyotype who are chemotherapy-naive tend to respond well to ibrutinib and rituximab. For those with genetic abnormalities, a clinical trial should be a priority.

“Using novel combinations prior to chemotherapy, such as doublets or, more likely, triplets like rituximab/lenalidomide/ibrutinib, leads to a very high complete response rate upfront and might offer new options for patients with molecular features that place them at high risk,” said Dr. Goy. [Editor’s Note: The NCCN Guidelines do not currently recommend this combination for induction therapy.]

Key Toxicities

Because patients receiving the SHINE regimen tend to be older and more frail, with multiple comorbidities, Camille Ballance, MSN, FNP-BC, a hematology-oncology nurse practitioner with Sarah Cannon Cancer Institute, in Nashville, emphasizes patient education about the potential toxicities associated with chemoimmunotherapy.

“Chemotherapy kills good cells and bad cells,” said Ms. Ballance. However, she noted, side effects associated with the bendamustine/rituximab combination tend to be all or nothing. “People either seem to do well, with very few side effects, or they struggle.”

Ms. Ballance prepares patients for potential nausea, vomiting, and diarrhea and cautions that fatigue may be a constant—especially when patients are receiving the chemotherapy portion of the regimen. Ms. Ballance also underscored the importance of close monitoring of patients who are receiving the monoclonal antibody rituximab for the first time.

“Bendamustine does not take long to administer and is given on days 1 and 2 [of a 28-day cycle], but rituximab is given intravenously the first day over a long period to try to reduce adverse reactions,” she explained to JNCCN 360. “Infusion reactions are common if patients have never received rituximab before or if it’s been more than 6 months, but typically, after the first dose, reactions are rare.”

Premedications, such as diphenhydramine, acetaminophen, and dexamethasone, are given with bendamustine plus rituximab along with antinausea medications, such as palonosetron or aprepitant. Because nausea is common, said Ms. Ballance, providers must be sure patients are receiving proper nutrition and staying hydrated. Occasionally, patients need to be brought to the clinic to receive intravenous fluids and/or additional antinausea medication, but dose reductions of bendamustine/rituximab for gastrointestinal issues are rare.

“Unless the symptoms are extreme, we tend not to dose reduce, because we’re trying to put patients into remission,” Ms. Ballance emphasized.

“It’s important to make sure that patients have good nausea medications at home and that they know they can come to the clinic for fluids,” she added. “The team is here to support them.”

It’s important to make sure that patients have good nausea medications at home and that they know they can come to the clinic for fluids.

Ms. Ballance also emphasized the importance of monitoring for infections and bleeding. “Patients with blood cancer are immunocompromised already,” she explained. “Then, on top of that, we give chemotherapy, which brings down their immune system and their platelets even more. It’s important for both patients and their family members to be aware of the risks of infection.”

With ibrutinib, arthralgia is an issue that can lead to noncompliance, and providers should monitor for atrial fibrillation and hypertension. Rashes are also common with the BTK inhibitor and may occasionally require providers to hold medications. Ibrutinib can exacerbate diarrhea, as well, said Ms. Ballance, who recommended loperamide to start. Patients with serious heart disease or uncontrolled arrhythmia should consult with a cardiologist or cardio-oncologist before starting on ibrutinib, she added.

Pharmacy Plays an Important Role

Treating patients with mantle cell lymphoma requires a multidisciplinary effort, said Ms. Ballance, but the pharmacy plays a particularly important role in ensuring compliance while helping to reduce financial toxicity.

The pharmacy plays a particularly important role in ensuring compliance [with the SHINE regimen] while helping to reduce financial toxicity.

“Our pharmacy follows up every month to make sure patients are receiving their drugs, and if they haven’t filled their prescription, the pharmacy will let us know,” she explained. “We also have an entire department of people who work on getting copay assistance for oral therapies, because some of these drugs can cost more than $1,000 per month out of pocket.”

“The pharmacy also keeps us informed regarding potential drug interactions,” Ms. Ballance said. “And, of course, the nurses help to keep everything in motion, handling infusions, watching for reactions and potential side effects, and communicating with physicians and advanced practice providers about additional patient care when it’s needed.”

Clinical Pearl: Start With Four Pills

According to Ms. Ballance, dosing for ibrutinib is typically 560 mg orally once daily. However, the drug also comes in 140-mg tablets. When initiating therapy, Ms. Ballance noted it can be helpful to start with four tablets per day (4 x 140 mg) instead of one (560-mg) tablet, given the potential for side effects.

“If patients start to have a rash or severe arthralgias, you can hold the ibrutinib part of the regimen and then titrate them back to the full dose as tolerated,” suggested Ms. Balance. She noted that fatigue also tends to improve with a break from the drug and/or dose reduction, but that it is rare to adjust medication for that reason specifically.

“Once the side effects have been managed, patients can then switch to one tablet, so they don’t have to swallow four tablets per day,” she added.

5 Surprisingly Simple Ways to Detoxify

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Simply incorporating a good apple—that is to say, 100 percent organic, nonirradiated, etc.—into your daily diet should constitute an extremely pleasurable experience. (Dean Drobot/Shutterstock)

Simply incorporating a good apple—that is to say, 100 percent organic, nonirradiated, etc.—into your daily diet should constitute an extremely pleasurable experience.

Given what we are exposed to through food, air, and water, detoxification has become a modern-day necessity. Without the daily activation of ancient, effective physiological pathways designed to remove naturally occurring environmental toxins or manmade chemical toxicants, we are bound to get sick.

So what are some simple, effective ways to rid our body of its daily toxic burden?

1) Pop a Probiotic

Of course, you don’t have to “pop a pill” to get a probiotic. In fact, it is preferred you ingest either a probotically cultured food (e.g. kombucha, yogurt [preferably plant-based], cultured veggies, etc.) or eat more raw fruits and vegetables grown in truly healthy soil, as the Earth’s microbiome is where “good bacteria” come from.

How will getting probiotics help? Fascinating research indicates that probiotics actually help us break down foods (e.g. gluten, casein) and chemicals (pesticides, Bisphenol A [BPA]) which can harm our bodies and which our own detoxification pathways do not handle effectively. It’s kind of a wonder that germs can help save us from ourselves in this way!

Epoch Times Photo
The reality is that we are meant to move our bodies, the result of which is the release of profoundly uplifting and regenerative hormonal and neurochemical secretions. 

2) Break a Sweat

Sadly, sweating has become synonymous with something gross that should be blocked with antiperspirants/deodorants—which ironically only further exacerbates the problem of body odor, as these keep one of your primary channels of detoxification from doing its job.

The reality is that we are meant to move our bodies, the result of which is the release of profoundly uplifting and regenerative hormonal and neurochemical secretions. And this is just the obvious “reward” we receive by pushing ourselves through the discomfort of sustained, intense bodily exertion to the point where we are profusely sweating.

Deeper benefits include the activation of the lymphatic system, which, while it is a part of the circulatory system, lacks a pump (like the heart) to push the lymphatic fluid through. This means the lymphatic system requires the activation of our entire skeletal musculature via exercise.

While one does not necessarily need to break a sweat to move the lymph (walking will suffice), you can “free two birds with one hand” by eliminating various heavy metals and chemicals via profuse sweating if you bring your physical activity toward that threshold, which incidentally overlaps with that sweet spot that activates feel-good secretions.

3) Don’t Break the Fast

In wealthier countries, where we suffer from the Orwellian paradox of being incredibly overnourished and simultaneously dying of nutritional deficiencies, one of the best ways to optimize your detoxification systems is to stop eating before sundown (which, I believe, is hard-wired into our bodily design) and skip your breakfast entirely. In other words, skip breakfast and continue through your day until you are truly hungry (not craving nutritionally dead gunk, or confusing the putrefaction-associated acidity of last night’s poorly digested or poorly food-combined dinner with an actual need to eat more), wherein you’re eating something wholesome, organic, and preferably living to get your fill.

If you eliminate and/or minimize the consumption of nutritionally vapid foods such as processed grain products and beans (soybean, peanut, and other “vegetable oils”) and have a salad, eat an apple, or consume some organic nuts, etc., then focus on eating one really good meal later in the day, you will be surprised by how little you will be hungry. Much of that craving is a byproduct of chronically elevated insulin, which is largely caused by overconsumption of processed, grain-based foods, and/or simple carbohydrates way beyond what you need to replenish your glycogen stores.

This doesn’t have to be painful. If you wake in the morning, have your cup of coffee or tea (if you imbibe), and feel that hunger and low energy driving you toward French toast, or whatever you would normally eat, try taking a couple of tablespoons of coconut oil. This will provide you (and your grumpy morning brain) with a near-immediate source of fuel. Sixty-six percent of coconut oil is medium-chain triglycerides that your body can use for energy very quickly, and that your liver breaks down into ketone bodies for your brain. Ketone bodies are the brain’s only other source of energy beyond glucose.

Of course, this is not going to work for everyone, but it certainly may fit better into a busy lifestyle than the “heroic fast” concept of just not eating anything at all—which has its place, especially for the very sick under professional guidance, or those on a spiritual mission. Heroic fasting does not suit those with kids, several jobs, and who just want a way to jumpstart the internal house-cleansing, metabolism-boosting process.

Garlic Peeling Hacks Used by Restaurant Chefs-tribunecontent
If you LOVE garlic, great. You are already a step ahead of those who only tolerate it. In the former case, you might want to ratchet up your romance a bit. In the latter case, don’t ignore its potential application in foods you are already enjoying.

4) Spice Up Your Life! 

Basic culinary spices can work wonders to stimulate bodily detoxification. A recent study, which we highlighted in the article, “Garlic Beats Drug in Safely Detoxifying Lead from the Body,” illustrates how you can use your food as medicine. If you LOVE garlic, great. You are already a step ahead of those who only tolerate it. In the former case, you might want to ratchet up your romance a bit. In the latter case, don’t ignore its potential application in foods you are already enjoying. The point is that we have plenty of help all around us, in our kitchen cupboards, on our spice racks, etc. And do you know what’s cool? There is a huge list of spices, foods, and nutrients—over 75, last time we counted—that we have indexed on GreenMedInfo.com that can stimulate detoxification pathways in the body.

5) An Apple a Day Isn’t Going Away

One of the most amazing nutritional stories of our time is what happened to tens of thousands of so-called “Chernobyl Children” after the meltdown of that reactor. In our article, “Why Apple Is One of the World’s Most Healing Superfoods,” we discuss the radioisotope-detoxifying properties of this incredible healing agent:

“Post-Chernobyl, for instance, apple pectin was used to reduce Cesium-137 levels in exposed children, in some cases by over 60 percent.[x] From 1996 to 2007, a total of more than 160,000 “Chernobyl” children received pectin food additives. As a result, levels of Cs-137 in children’s organs decreased after each course of pectin additives by an average of 30–40 percent.[xi] Significant reductions were noted in as short a time period as 16 days.[xii] Apple pectin has even been found to prevent the most deadly, and entirely manmade radioisotope, Plutonium-239, from absorbing in the gastrointestinal tract of animals fed it.[xiii]“

The great thing about an apple, of course, is that it’s a whole food. Rather than take mega-doses of apple pectin (assuming you don’t live in Fukushima or were exposed to its fallout in some way; otherwise, please do!), simply incorporating a good apple—that is to say, 100 percent organic, nonirradiated, etc.—into your daily diet should constitute a pleasurable experience (especially if you incorporate this healthy snack as the “break” in our no break-the-fast strategy). We can be nourished, pleasured, and detoxified all in one act; and this is indeed the way nature designed things, in its inexhaustible wisdom.

Lastly, but perhaps most importantly, please avoid getting poisoned in the first place. Easier said than done, I understand. But here are some important things to remember to make sure you aren’t unintentionally throwing yourself on a chemical grenade every day.

Unless you need your receipts, don’t take them.

Next to canned food (with that darn alphabet soup of bisphenols in its can liners—yeah, it’s not just BPA, but BPS and others the industry is now using), receipts are the primary route of exposure to this profoundly damaging class of gender-bending, heart-damaging, brain-damaging petrochemicals. Avoid touching thermal printer receipts—especially if you use lotion, which only accelerates the skin’s absorbance of these chemicals.

Stop slathering petrochemicals on your body.

If you are putting it on your skin, it’s likely worse than eating it. How’s that? Unlike what you put into your mouth, where your liver determines whether it will be allowed into your bloodstream, your skin has no such guardian to keep poisons out. If something you are using as a body care product has an ingredient that requires a degree in chemistry to understand, ditch it (that is, recycle it), or don’t buy it. If you can’t eat an ingredient, don’t put it on your body. Even better, try using coconut oil or related food-cosmetic medicines, with thousands of years of prior use backing up their effectiveness and safety.

Don’t drink the water.

If you get your water through a municipal system, and it hasn’t been effectively purified (ideally, distilled with minerals reintroduced), you shouldn’t drink it. Also keep in mind that you can get pristine water from Iceland or Fiji (or wherever marketers like to take our imagination), but if it’s been sitting in plastic for a year, it’s not as good as it would seem due to the widespread contamination of plastic bottles with microplastics. The problem with municipal drinking water isn’t just the fluoride residues, but with the 600-plus disinfectant byproducts it carries, all of which are known to be toxic to the body, damage DNA, and probably contribute to cancer. It still boggles my imagination that anyone would willfully expose themselves to this, even in its secondary iteration as cooking water, i.e. using it to make pasta. Water composes the majority of our bodies. Learn to savor “biological water,”—that is, water that comes from pure food, e.g. watermelon. This water is “structured” by the universe itself, and is unparalleled in what it can do for your body.

So we’ve covered some problems and solutions; certainly, this is just the tip of the iceberg. Just take it all with a grain of sea salt, and take what works for you and leave the rest.

Blueberry–A Natural Vascular Scavenger That Helps Prevent Heart Disease

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Studies have found that people who consume blueberries have lower lipid peroxidation in their blood lipids, and fewer inflammation responses. (Shutterstock)

Studies have found that people who consume blueberries have lower lipid peroxidation in their blood lipids, and fewer inflammation responses. (Shutterstock)

A long-time friend of mine suddenly died of a heart attack while using the bathroom at home. I wondered—what caused his heart attack and why did it come on so suddenly and viciously? How should we deal with this disease? Can diet help us to reduce the risk of heart disease?

My friend was a wonderful person who took his work very seriously. He became busier as he got better at his job and was promoted to higher positions, often working until very late at night. When I visited him at his home, I often noticed the presence of bread, instant noodles, and all kinds of snacks piled up on the table.

He was obese, with mental stress, and had an unhealthy diet, which may have led to his various health problems. People who regularly function as he did generally have higher blood lipids, blood sugar, and blood pressure. Had my friend not succumbed to an early heart attack, his unhealthy lifestyle may have led to atherosclerosis.

Causes and Consequences of Atherosclerosis

Atherosclerosis is a chronic inflammatory disease in which there is a build-up of plaques inside arteries. It is principally a lipid-driven process initiated by the accumulation of low-density lipoprotein and remnant lipoprotein particles and an active inflammatory process in focal areas of arteries, particularly at regions of disturbed non-laminar flow at branch points in the arteries.

Atherosclerosis is considered a primary cause of atherosclerotic cardiovascular disease resulting in heart attacks, stroke, and peripheral arterial disease. According to NIH, Atherosclerosis is the underlying cause of about 50 percent of all deaths in western society.

Ways to Prevent Atherosclerosis

Steps to fighting this disease include changing our sedentary lifestyle to include exercise. We also need to control our weight, improve our diet and reduce stress. Those with a family history of heart disease should be especially proactive in the maintenance of health.

Implementation of the above can help to prevent heart disease by properly regulating blood sugar, blood lipids, blood pressure, and weight.

Once the blood vessel wall has been damaged, platelets, clotting factors (such as fibrinogen and prothrombin) and cholesterol accumulate at the site, resulting in blockage of the blood vessels. Myocardial infarction (heart attack) occurs when the heart’s blood vessels are constricted. A blocked blood vessel in the brain is a cerebral infarction, which causes necrosis of brain tissue.

Fortunately, eating berries can help clear blood clots. There are a variety of berries, such as strawberries, blueberries, blackberries, and raspberries that in addition to lowering cholesterol, improve the function of the arteries. Blueberries, in particular, are rich in vitamins, fiber, trace elements, and antioxidants such as polyphenols.

Blueberries Lower Inflammation and Prevent Heart Disease

A study on blueberries and cardiovascular risk factors in obese men and women was published in 2010 in “The Journal of Nutrition.” The study divided people into two groups. One group was given blueberry juice made from 50 grams of frozen blueberries and 350 grams of fresh blueberries every day for eight weeks. The control group was given water to drink. At weeks four and eight of the experiment, the researchers measured the participant’s blood glucose, blood lipids, and various inflammatory markers. The data showed that the blueberry drinkers had lower lipid peroxidation and lower inflammation responses.

Why do blueberries have such a beneficial effect? Scientists have found that blueberries can reduce the inflammatory response through antioxidant effects, and reduce the accumulation of cholesterol in blood vessels by affecting the metabolism and transport of cholesterol. Blueberries can also protect endothelial cells by affecting the function of vascular endothelial cells.

Damage to endothelial cells is the main cause of infarction—once the blood vessel wall is broken, anything can be deposited in it, not only cholesterol. Thus, myocardial infarction is caused by more than just high cholesterol.

What is the cause of damage to the blood vessel wall? High blood pressure, diabetes, and chronic inflammation can damage the blood vessel walls. The good news is that blueberries can improve all of these conditions.

Blueberries can also improve the role of intestinal flora, and act as a probiotic to help adjust the flora of our intestines. The health of our intestinal tract is very important. If the intestinal flora is imbalanced, it can cause intestinal leakage, allowing toxins to enter the bloodstream.

Remember to add blueberries and other berries to your diet to improve the health of your heart.

Closer to 3D Printing Life-Like Organs

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Summary: Researchers have developed a new technique that transforms medical images from MRI scans into detailed 3D computerized models. This new advance is an important step toward creating realistic 3D models of human organs for research and medical training.

Source: University of Colorado

A team of University of Colorado researchers has developed a new strategy for transforming medical images, such as CT or MRI scans, into incredibly detailed 3D models on the computer.

The advance marks an important step toward printing lifelike representations of human anatomy that medical professionals can squish, poke and prod in the real world.

The researchers describe their results in a paper published in December in the journal 3D Printing and Additive Manufacturing.

The discovery stems from a collaboration between scientists at CU Boulder and CU Anschutz Medical Campus designed to address a major need in the medical world: Surgeons have long used imaging tools to plan out their procedures before stepping into the operating room. But you can’t touch an MRI scan, said Robert MacCurdy, assistant professor of mechanical engineering and senior author of the new study. 

His team wants to fix that, giving doctors a new way to print realistic, and graspable, models of their patients’ various body parts, down to the detail of their tiny blood vessels—in other words, a model of your very own kidney entirely fabricated from soft and pliable polymers.

“Our method addresses the critical need to provide surgeons and patients with a greater understanding of patient-specific anatomy before the surgery ever takes place,” said Robert MacCurdy, senior author of the new paper and an assistant professor of mechanical engineering at CU Boulder.

The latest study gets the team closer to achieving that goal. In it, MacCurdy and his colleagues lay out a method for using scan data to develop maps of organs made up of billions of volumetric pixels, or “voxels”—like the pixels that make up a digital photograph, only three-dimensional.  

The researchers are currently experimenting with how they can use 3D printers to turn those maps into physical models that are more accurate than those available through existing tools.

The project, which is led by MacCurdy and CU Anschutz’ Nicholas Jacobson, is funded by AB Nexus, a grant program that seeks to spur new collaborations between the two Colorado campuses.

“In my lab we look for alternative ways of representation that will feed, rather than interrupt, the thinking process of surgeons,” said Jacobson, a clinical design researcher at the Inworks Innovation Initiative. “These representations become sources of ideas that help us and our surgical collaborators see and react to more of what is in the available data.”

Slicing the orange

Human organs are complicated—made up of networks of tissue, blood vessels, nerves and more, all with their own texture and colors. 

Currently, medical professionals try to capture these structures using “boundary surface” mapping, which, essentially, represents an object as a series of surfaces.

This shows a cross section of a kidney
Voxel map of a cross section of a human kidney.

“Think of existing methods as representing an entire orange by only considering the exterior orange peel,” MacCurdy said. “When viewed that way, the entire orange is peel.”

His team’s method, in contrast, is all juicy insides.

The approach begins with a Digital Imaging and Communications in Medicine (DICOM) file, the standard 3D data that CT and MRI scans produce. Using custom software, MacCurdy and his colleagues convert that information into voxels, essentially slicing an organ into tiny cubes with a volume much smaller than a typical tear drop. 

And, MacCurdy said, the group can do all that without losing any information about the organs in the process—something that’s impossible with existing mapping methods.

To test these tools, the team took real scan data of a human heart, kidney and brain, then created a map for each of those structures. The resulting maps were detailed enough that they could, for example, distinguish between the kidney’s fleshy interior, or medulla, and its outer layer or, cortex—both of which look pink to the human eye. 

“Surgeons are constantly touching and interacting with tissues,” MacCurdy said, “So we want to give them models that are both visual and tactile and as representative of what they’re going to face as they can be.”

Abstract

Defining Soft Tissue: Bitmap Printing of Soft Tissue for Surgical Planning

Nearly all applications of 3D printing for surgical planning have been limited to bony structures and simple morphological descriptions of complex organs due to the fundamental limitations in accuracy, quality, and efficiency of the current modeling paradigms and technologies.

Current approaches have largely ignored the constitution of soft tissue critical to most surgical specialties where multiple high-resolution variations transition gradually across the interior of the volume. Differences in the scales of organization related to unique organs require special attention to capture fine features critical to surgical procedures.

We present a six-material bitmap printing technique for creating 3D models directly from medical images, which are superior in spatial and contrast resolution to current 3D modeling methods, and contain previously unachievable spatial fidelity for soft tissue differentiation.

FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma

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the Food and Drug Administration (FDA) granted accelerated approval to pirtobrutinib (Jaypirca, Eli Lilly and Company) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

Efficacy was evaluated in BRUIN (NCT03740529), an open-label, multicenter, single-arm trial of pirtobrutinib monotherapy that included 120 patients with MCL previously treated with a BTK inhibitor. Patients had a median of 3 prior lines of therapy, with 93% having 2 or more prior lines. The most common prior BTK inhibitors received were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%); 83% had discontinued their last BTK inhibitor due to refractory or progressive disease. Pirtobrutinib was administered orally at 200 mg once daily and was continued until disease progression or unacceptable toxicity.

The main efficacy measures were overall response rate (ORR) and duration of response (DOR), as assessed by an independent review committee using Lugano criteria. The ORR was 50% (95% CI: 41, 59) with a complete response rate of 13%. The estimated median DOR was 8.3 months (95% CI: 5.7, NE), and the estimated DOR rate at 6 months was 65.3% (95% CI: 49.8, 77.1).

The most common adverse reactions (≥15%) in patients with MCL were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities in ≥10% of patients were decreased neutrophil counts, lymphocyte counts, and platelet counts. The prescribing information includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies.

The recommended pirtobrutinib dosage is 200 mg orally once daily until disease progression or unacceptable toxicity.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review and fast track designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. The application also was granted orphan drug designation.

Why Do I Wake Up at 3am?

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Waking up at 3 a.m. and finding it difficult to fall back asleep can be a frustrating experience. Some people may wonder what might be causing this kind of sleep disruption and whether they should seek out help.

Waking up in the middle of the night or early morning, called nocturnal awakening or early morning awakening, is common. One U.S. study found 35.5% of people wake up in the middle of the night on three or more nights per week. A similar study conducted in multiple European countries found nearly one-third of people wake up three or more nights per week.

While it is not always possible to pinpoint the exact reason a person wakes up at 3 a.m, understanding common causes of sleep disruptions may help people sleep more soundly through the night. Learn about the various reasons a person might find themselves waking up at 3 a.m., as well as tips for better sleep and when to consult a doctor.

Sleep Environment Disturbances

Nighttime noise Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference , such as sounds from outdoor traffic, televisions, or cell phones, is a significant cause of disturbed sleep. Similarly, exposure to light Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference from an outdoor light shining through a window or even a dim nightlight can also cause a person to wake up during the night.

Waking up may be more likely in the early morning hours due to how the body advances through the stages of sleep. As a person moves through periods of light, deep, and rapid eye movement sleep, more time is spent in light sleep as the night progresses. A person in light sleep is more easily awakened from environmental noise.

Bathroom Breaks

Sometimes, when a person wakes up during the night they feel a need to urinate, which is referred to as nocturia. For many people, nocturia may be due to drinking too much liquid near bedtime, particularly coffee or alcohol. For others, nocturia may be the result of a bladder condition, urinary issues, or other health conditions like obstructive sleep apnea and diabetes. Nocturia is also common during pregnancy and usually goes away within a few months after giving birth.

Menopause

Hormonal changes during menopause can also cause disrupted sleep. Symptoms of menopause are caused by decreasing production of certain hormones Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference and often include nighttime and early morning awakenings. Some awakenings may coincide with hot flashes Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference , night sweats, or insomnia. For some, nighttime awakenings persist after menopause, due to continued hot flashes or an increased risk for obstructive sleep apnea.

Sleep Disorders

Sleep disorders are conditions that affect the quality, timing, and amount of sleep a person gets each night. Nocturnal awakenings are a symptom of several sleep disorders.

  • Insomnia: People with insomnia may have issues with sleep maintenance, or the ability to stay asleep throughout the night. In particular, nighttime awakenings that last for 30 minutes or more is a hallmark symptom of insomnia.
  • Obstructive sleep apnea (OSA): OSA causes lapses in breathing that may wake a person up during the night. As some people may not be aware of their OSA symptoms, they may feel they have woken up in order to urinate.
  • Circadian rhythm disorders: For people with circadian rhythm disorders, there is a misalignment between their internal clock and the environmental cues that trigger the body to be awake or asleep. Certain circadian rhythm disorders, like advanced sleep phase disorder and irregular sleep-wake rhythm, cause a person to wake up at unusual times.
  • Nightmare disorder: Nightmares are most likely to occur in the middle of the night or early morning and may wake a person up. Feelings of distress and worry from a nightmare may make it hard to fall back asleep, which can make obtaining quality sleep even more difficult.

Stress, Anxiety, or Depression

Some people are more likely to experience disrupted sleep during stressful times. This trait is called sleep reactivity Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference , and it can cause a person to have trouble staying asleep throughout the night. Females and people with certain inherited genetic traits are more likely to experience sleep reactivity. Stress reactivity is also more common in people who tend to focus their thoughts on the things that cause stress.

Studies show that people with post-traumatic stress disorder (PTSD) Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference are likely to experience disrupted sleep during the night. Nighttime awakenings may be more common in the early years of PTSD and become less frequent over time. Trouble staying asleep through the night is also common in people with other anxiety disorders, including panic disorder and phobias.

Trouble sleeping is a common symptom in people with major depression. Experts suspect that depression impacts sleep by altering a person’s circadian rhythm, or the internal body clock that regulates the sleep-wake schedule Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference . When the internal body clock is disrupted, a person might find themselves feeling alert at times they would normally be asleep.

Health Issues and Medications

A variety of health issues are associated with waking up during the night.

  • Pain: Physical pain can make it hard to have a restful night of sleep for a number of reasons. A recent study observed that those dealing with pain were four times more likely to have trouble falling back to sleep after a nighttime awakening.
  • Heart and vascular conditions: High blood pressure, heart disease, and stroke are associated with poor quality sleep, including waking up during sleep.
  • Airway diseases: In addition to obstructive sleep apnea, other breathing disorders like asthma and chronic obstructive pulmonary disease (COPD) can disrupt sleep through the night.
  • Endocrine disorders: Diabetes, vitamin D deficiency, and hyperthyroidism are among a number of hormone disorders that are associated with poor quality sleep.
  • Neurological disorders: Although it is normal to undergo a number of changes to sleep patterns as people age, those with conditions like dementia Trusted Source UpToDate More than 2 million healthcare providers around the world choose UpToDate to help make appropriate care decisions and drive better health outcomes. UpToDate delivers evidence-based clinical decision support that is clear, actionable, and rich with real-world insights. See Full Reference , Alzheimer’s disease, and Parkinson’s disease are more likely to experience nighttime awakenings and have trouble returning to sleep .

Additionally, some medications used to treat health issues, like corticosteroids and diuretics, can also cause nighttime awakenings.

Aging

A person’s circadian rhythm changes with age, making early-morning awakenings more common in older adults. In fact, it is common for older adults to wake up three to four times Trusted Source Medline Plus MedlinePlus is an online health information resource for patients and their families and friends. See Full Reference every night .

Older adults spend less of their sleep time in deep sleep, which may contribute to waking up more easily during the night. Other causes of age-related sleep changes include nocturia, anxiety, and symptoms of chronic health issues.

Tips for Sleeping Through the Night

People whose sleep is disrupted by waking up at 3 a.m. can try following healthy sleep tips to sleep through the night more consistently.

  • Avoid caffeine and alcohol: Both caffeine and alcohol are associated with disrupted sleep, especially when they are consumed later in the day. These substances may leave a person having trouble falling asleep and more likely to need to wake up to urinate.
  • Increase daytime light exposure: Exposure to sunlight or a bright lamp may help some people sleep better at night and feel more alert during the day. Studies have found bright light therapy Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference to benefit people with general sleep problems, circadian rhythm disorders, insomnia, and sleep issues related to Alzheimer’s and dementia.
  • Try exercise or yoga: Engaging in regular exercise, preferably earlier in the day, may improve sleep. One study found that daytime yoga Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference in particular is associated with less time awake in bed during the night and improves the ability to fall back asleep more quickly after a nocturnal awakening.
  • Avoid evening meals: A recent survey suggests that late meal timing Trusted Source National Library of Medicine, Biotech Information The National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information. See Full Reference can increase a person’s likelihood of awakening during the night. Although more research is needed, people experiencing nocturnal awakenings may want to avoid eating in the three hours before sleep.
  • Keep the bedroom dark and quiet: Environmental disturbances, like noise and light, can wake a person from nighttime sleep. If darkness and quiet are not possible, wearing a sleep mask to block out light and earplugs to block out sound can help.

When to Talk to Your Doctor

Although nighttime awakenings are common and generally easy to remedy, they may also be a sign of a larger issue. If you feel that sleep disruptions are affecting your quality of life or if you are experiencing symptoms of other health problems, you may find it helpful to consult with a doctor to rule out an underlying disorder. Older adults who are experiencing nighttime awakenings are encouraged to talk to their doctor about how to reduce the risk of falls or accidents that could occur when getting out of bed at night.

FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer

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On January 27, 2023, the Food and Drug Administration (FDA) approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with elacestrant.

Efficacy was evaluated in EMERALD (NCT03778931), a randomized, open-label, active-controlled, multicenter trial that enrolled 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer of which 228 patients had ESR1 mutations. Patients were required to have disease progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. Eligible patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting. Patients were randomized (1:1) to receive elacestrant 345 mg orally once daily (n=239) or investigator’s choice of endocrine therapy (n=239), which included fulvestrant (n=166) or an aromatase inhibitor (n=73). Randomization was stratified by ESR1 mutation status (detected vs. not detected), prior treatment with fulvestrant (yes vs. no), and visceral metastasis (yes vs. no). ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain.

The major efficacy outcome measure was progression-free survival (PFS), assessed by a blinded imaging review committee. A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with ESR1 mutations.

In the 228 (48%) patients with ESR1 mutations, median PFS was 3.8 months (95% CI: 2.2, 7.3) in the elacestrant arm and 1.9 months (95% CI: 1.9, 2.1) in the fulvestrant or aromatase inhibitor arm (hazard ratio [HR] of 0.55 [95% CI: 0.39, 0.77], 2-sided p-value=0.0005).

An exploratory analysis of PFS in the 250 (52%) patients without ESR1 mutations showed a HR 0.86 (95% CI: 0.63, 1.19) indicating that the improvement in the ITT population was primarily attributed to the results seen in the ESR1 mutated population.

The most common adverse events (≥10%), including laboratory abnormalities, were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.

The recommended elacestrant dose is 345 mg taken orally with food once daily until disease progression or unacceptable toxicity.

Covid-19: What do we know about XBB.1.5 and should we be worried?

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What is XBB.1.5?

XBB.1.5 is yet another omicron subvariant, and follows on from XBB and XBB.1. Scientists have nicknamed it “kraken” to distinguish it from the “variant soup” we are all navigating three years into the pandemic.1 The X signifies that these subvariants came about through a recombination of two or more sublineages—in this case BA.2.10.1 and BA.2.75.2

According to UCL Genetics Institute director Francois Balloux, a professor of computational systems biology, XBB.1.5 differs from XBB.1 through the addition of a F486P mutation in the spike protein. “This mutation makes it slightly less immune evasive than its XBB.1 ancestor but more infectious, probably because it increases binding affinity to the human cell receptor ACE-2,” he said.

Where is XBB.1.5 spreading?

The World Health Organization has reported that XBB.1.5 is present in 38 countries.3

The UK Health Security Agency (UKHSA) said it is one of two variants most likely to become dominant in the UK, despite representing less than 5% of all SARS-CoV-2 samples sequenced in the last week of 2022. The agency has described the variant as having a combination of “immune escape properties” and a higher ACE-2 binding affinity, which it said could lead to higher transmissibility. “It is plausible that XBB.1.5 will cause an increase in incidence after the current wave, however it is currently too early to confirm this trajectory,” UKHSA said.4

Meanwhile, the European Centre for Disease Prevention and Control (ECDC) has said there is a “moderate probability” that XBB.1.5 will become dominant across the European Union and European Economic Area and cause a “substantial increase in the number of covid-19 cases within the next one to two months.”

In the US the Centers for Disease Control and Prevention has said the variant is “spreading quickly” and is estimated to make up around 28% of cases in the country (week ending 7 January 2023).

“XBB.1.5 is widely anticipated to go up in frequency globally, and may cause a sizeable fraction of cases globally in the near future,” Balloux said. “That said, it remains questionable whether XBB.1.5 will cause a major wave on its own.”

Does it cause more severe illness?

This is still under review. According to WHO, however, XBB.1.5 “does not carry any mutation known to be associated with potential change in severity.” This appears to be supported by the ECDC, which said that there are no indications that XBB.1.5 will be any more severe than the other omicron sublineages that have circulated.

Do the current covid vaccines protect against XBB.1.5?

Specific vaccine effectiveness estimates are not yet available for XBB.1.5, but WHO has warned that it may have the “highest immune escape to date.” Its evidence suggests people who have had three or four doses of an mRNA covid-19 vaccine (such as Moderna or Pfizer) plus a BA.5 infection, or three doses of the Chinese Coronavac vaccine plus previous infection with BA.1, BA.5, or BF.7 “do not induce high neutralisation titers against XBB.1.5.5.”

The ECDC has also warned that its predecessors—XBB and XBB.1—showed “significant reductions in the neutralising capacity of serum from vaccinated people.” Despite this, the agency has said the available vaccines “still remain effective against severe disease because of previous and current omicron variants dominant in the EU, even though there is some evidence of waning over time.”5

It is not yet clear whether an XBB-specific booster vaccine could be needed, but experts have called on those eligible to get available booster vaccines where possible.

Is XBB.1.5 a cause for concern?

While much of the evidence surrounding XBB.1.5 is still being collected and reviewed, experts have said there is currently no need to be alarmed by this variant.

Ashall professor of infection and immunity at the University of Oxford Andrew Pollard, who led the team that developed the Oxford AstraZeneca vaccine, told The BMJ, “We should be cautious not to drive fear that each new variant heralds a new crisis in the pandemic. There is no reason to think that XBB.1.5 is of any more concern than other variants that come and go in the ever changing landscape of covid-19 mutants.”

Pollard said that, in the UK at least, the focus needs to be on ensuring the healthcare system can cope with not just covid-19, but all patients.

“In the UK today, the problem is not new infections with covid-19, which is just one of many non-pandemic viruses that make us sick, but the chronic shortage of capacity, funding, and staff in our health and social care system. We have to plan for expected winter pressures from infections and need to develop the resources to accommodate a growing elderly population over the decades ahead,” he said. “These are not easy problems to solve but, unlike pandemics, they are not easily solved by leaps in science or short term fixes but by a long term vision for our health shared across the political divide.”