Cobimetinib (Cotellic), an oral MEK inhibitor, has received FDA approval for the treatment of patients with histiocytic neoplasms, includingErdheim-Chester disease, Rosai-Dorfman disease, and Langerhans cell histiocytosis.

The regulatory decision was based on data collected through a collaborative effort between Memorial Sloan Kettering (MSK) Cancer Center and Genentech. Data from the single-center, single-arm trial showed that at a median follow-up of 11.4 months (range, 0.2-36.8), cobimetinib elicited an objective response rate (ORR) of 76.9% (n = 20; 95% CI, 56.4%-91.0%) by PET and 46.2% (n = 12; 26.6%-66.6%) by RECIST criteria in 26 enrolled patients.

“The approval of cobimetinib represents the collective hard work of several years of investigation by many MSK researchers. There have been tremendous advances in the field of rare cancers as a result of research and trials conducted at MSK, and this approval is an excellent example of a practice-changing outcome,” Eli L. Diamond, MD, principal investigator of the trial, neurooncologist, and neurologist at MSK, stated in a press release. “There has always been an unmet need for patients with histiocytosis, and we are thrilled that with this approval, these patients will now have access to a viable treatment option.”

The trial enrolled adult patients with histologically confirmed histiocytic neoplasms of any mutational status. Notably, those with documented 

 V600E mutations were permitted if they were unable to access a BRAF inhibitor or if they discontinued a BRAF inhibitor because of toxicity.

All participants had multisystem disease, recurrent or refractory disease, or single-system disease that was determined to be unlikely to benefit from conventional treatments, based on best available evidence.

Of the 26 patients enrolled to the trial, 4 had Langerhans cell histiocytosis, 4 had Rosai-Dorfman disease, 13 had Erdheim-Chester disease, 2 had xanthogranuloma, and 3 had mixed histiocytosis. The median age was 50.5 years (range, 18-79); 65% (n = 17) were male and 85% were White. The majority of patients (n = 20), had 

Study participants were administerd cobimetinib at a once-daily dose of 60 mg as part of a 21-days-on/7-days-off schedule in a 28-day cycle.

Best ORR (BORR) served as the main efficacy outcome for the trial. Other clinical outcomes of interest comprised duration of response (DOR) and BORR maintained on 2 occasions at least 4 weeks apart.

Additional data showed that the median time to response with cobimetinib was 2.0 months (range, 0.2-17.3) and the median DOR was 31 months (range, 2-31).

“Until now, no standard therapy has existed for the 50% of histiocytosis patients without the 

 mutation,” Omar Abdel-Wahab, MD, hematologic oncologist and director of the Center for Hematologic Malignancies at MSK, added in the press release. “The research pioneered at MSK has led to a viable treatment option for adult patients who harbor this mutation. Looking ahead, we are working on advancing treatment options for pediatric patients with histiocytosis as we have done in adults.”

FDA approves oral MEK inhibitor cobimetinib for histiocytic neoplasms, research led by Memorial Sloan Kettering Cancer Center. News release. Memorial Sloan Kettering Cancer Center. November 1, 2022. Accessed November 2, 2022. https://bit.ly/3TZQPzv

Cotellic. Prescribing information; Genentech; 2022. Accessed November 2, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/206192s005lbl.pdf

Articles

Cobimetinib is now an FDA-approved therapy for patients with histiocytic neoplasms. 

Oral MEK Inhibitor, Cobimetinib, Receives FDA Approval for Histiocytic Neoplasms

Monitoring a patient’s phosphorus levels may be an effective way to anticipate the development of severe immune effector cell–associated neurotoxicity syndrome (ICANS) following CAR T-cell therapy, according to findings published in the 

American Association for Cancer Research Journal. 

The results suggest that patients who experience decreases in extracellular phosphorous are at an increased risk of developing hypophosphatemia and ICANS.

In individual patients, investigators observed that decreased in serum phosphorus within the threshold for clinical hypophosphatemia also overlapped with the onset of ICANS. Based on this observation, a linear mixed-effects model was developed, with serum phosphorus representing the outcome variable, and time from CAR T-cell infusion and ICANS grade/CARTOX-10 score representing the fixed effects of the model.

In this model, ICANS grade was negatively associated with serum phosphorous, and each unit decreased in ICANS grade was linked to a 0.29 mg/dL decrease in phosphorous (

< .001). CARTOX-10 score was positively associated with serum phosphorus, and each point of reduction corresponded to a 0.11 mg/dL decreased on phosphorous (

The relationship between phosphorous and both ICANS and CARTOX-10 diminished the longer the patient was post-infusion, indicating that the active agents were the drivers, or this serum phosphorus changes and consequent neurotoxicity.

“Despite their clinical effectiveness, the serious [adverse] effects of CAR T-cell therapies often require escalation to an intensive care setting,” wrote Theodore Scott Nowicki, MD, PhD, assistant professor-in-residence in the Departments of Pediatrics (Hematology/Oncology) and Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA, and coinvestigators in the paper. “ICANS affects approximately 50% of all CAR T-cell recipients [and] the need for biomarkers of ICANS represents an important area of potential improvement in these therapeutic protocols.”

ICANS, commonly occurs concomitantly with cytokine release syndrome and is characterized by confusion, delirium, aphasia, impaired motor skills, and somnolence. In severe cases, seizures and comas may occur as well. Targeted therapies, such as anti-IL6 tocilizumab (Actemra), may be used to managed cytokine release syndrome (CRS), the bulk of ICANS management is supportive care with nonspecific immunosuppression—which may reduce the efficacy of CAR T-cell therapy. Because of this, authors identified an unmet need for predictive markers for ICANS.

Hypophosphatemia is a clinical anomaly which has been observed in patients who received CAR T-cell therapies or adoptive cell therapies. Hypophosphatemia is characterized by weakness, confusion, altered mental status, seizure, and coma. It is also associated with an acute increase in metabolic demand, which as with sepsis and refeeding syndrome. Hypophosphatemia occurs when cells suddenly need to consume high amounts of phosphate to synthesize certain substrates, this sudden redistribution of extracellular phosphorus results in these striking neurologic symptoms for patients.

Because the physical manifestations of hypophosphatemia manifest like ICANS, investigators hypothesized that an increase of metabolic activity and consequent extracellular phosphate consumption might be at play with both adverse events. They therefore sought to determine whether CAR T-cell engagement with targeted antigens results in an increased in metabolic activity and extracellular phosphate consumption.

Investigators retrospectively examined data from 77 patients who received CD19-targeted CAR T-cell therapy at UCLA. In this cohort, 23 patients (30%) developed ICANS following treatment. The median onset time was 5-days post infusion. Among these patients, 17 (86.7%) developed severe ICANS, defined as grade 2 or worse severity. ICANS development or severity was not linked to any patient characteristics, disease characteristics, or infusion product. Moreover, 69% of all patients developed ICANs.

Hypophosphatemia, defined as serum phosphate concentrations lower than 2mg/dL, was significantly associated with ICANS (

 = .0003). The median time to nadir for phosphorous was 5 days, which coincided with the median onset time of ICANS development. In addition, the median nadir serum phosphorus of the ICANS group was significantly lower than among those who did not develop ICANs (1.391 mg/dL vs 2.130 mg/dL; 

“In a clinical setting, decreases in patient serum phosphorus levels correlated with the incidence and severity of ICANS,” study authors concluded. “These results have implications for monitoring for the development of ICANS in the growing number of patients receiving adoptive cell therapies for cancer.”

Tang JP, Peters CW, Quiros C, et al. Hypophosphatemia due to increased effector cell metabolic activity is associated with neurotoxicity symptoms in CD19-targeted CAR T-cell therapy. 

. Published online October 19, 2022. doi:10.1158/2326-6066.CIR-22-0418

Following CAR T-cell therapy, the onset of hypophosphatemia may represent a biomarker for immune effector cell–associated neurotoxicity syndrome incidence and severity. 

Phosphorous Monitoring May Be Optimal for Detecting Serious ICANS in Patients Receiving CAR T-Cell Therapy

Teclistamab-cqyv (Tecvayli) has received accelerated approval from the FDA on the indication of adult patients with relapsed or refractory multiple myeloma. To be eligible for treatment, these patients must have already undergone 4 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (iMID), and an anti-CD38 monoclonal antibody.

The regulatory decision is supported by data from the phase 1/2 MajesTEC-1 trial (NCT03145181; NCT04557098), which showed that teclistimab elicited an objective response rate of 61.8% (95% CI, 52.1%-70.9%) by independent review committee assessment and utilizing International Myeloma Working Group 2016 criteria.

Moreover, at a median follow-up of 7.4 months in responders, the estimated duration of response rate (DOR) at 6 months with the agent was 90.6% (95% CI, 80.3%-95.7%); at 9 months, this rate was 66.5% (95% CI, 38.8%-83.9%). The median DOR was not estimable (NE; 95% CI, 9.0-NE).

The single-arm, open-label, multicenter trial enrolled patients who had received at least 3 prior treatments, including a PI, an iMID, and an anti-CD38 monoclonal antibody.

 Those who had stroke or seizure, or who had undergone an allogeneic stem cell transplantion within the past 6 months, were excluded. Other exclusion criteria included having an ECOG performance status of 2 or higher, known active central nervous system involvement or signs of meningeal involvement of the disease, or active or documented history of autoimmune disease.

Study participants received step-up doses of teclistamab at 0.06 mg/kg and 0.3 mg/kg followed by 1.5-mg/kg doses of the agent administered subcutaneously once weekly thereafter. Treatment was administered until progressive disease or intolerable toxicity.

The median age in the efficacy population (n = 110) was 66 years (range, 33-82), with 16% of patients aged 75 years or older. Moreover, 56% of patients were male and 91% were White. Regarding disease stage at study entry, per the International Staging System criteria, 50% had stage I disease, 38% had stage II disease, and 12% had stage III disease. Twenty-five percent of participants had high-risk cytogenetics in the form of the presence of del(17p), t(4;14), and t(14;16). Further, 17% of patients had extramedullary plasmacytomas. Notably, those who previously received BCMA-targeted therapy were excluded from the efficacy analysis.

Patients were heavily pretreated, with 78% of patients having received at least 4 prior lines of therapy. The median nuymber of prior lines of treatment received was 5 (range, 2-14). Notably, 76% of patients were triple-class refractory.

ORR served as a major efficacy outcome measure for the trial. Key secondary outcomes measures comprised DOR, very good partial response (VGPR) or better rate, complete response (CR) or better rate, stringent CR rate, time to response, progression-free survival, and overall survival, among others.

Additional data showed that of those who responded to treatment, the CR or better rate was 28.2%, the VGPR rate was 29.1%, and the PR rate was 4.5%. The median time to first response was 1.2 months (range, 0.2-5.5).

Among the 165 patients who received teclistimab, 47% were exposed to the drug for at least 6 months; 7% were exposed for at least 1 year. In the safety population, the median age was 64 years (range, 33-84); 58% of patients were male and 81% were White.

Fifty-four percent of patients who received teclistimab experienced serious adverse effects. Serious adverse reactions that occurred in more than 2% of patients included penumonia (15%), cytokine release syndrome (CRS; 8%), sepsis (6%), general physical health deterioration (6%), COVID-19 (6%), acute kidney injury (4.8%), pyrexia (4.8%), musculoskeletal pain (2.4%), and encephalopathy (2.4%).

Five percent of patients experienced fatal adverse reactions, which were due to COVID-19 in 1.8% of patients, pneumonia in 1.8%, septic shock in 0.6%, acute renal failure in 0.6%, and hemoperitoneum in 0.6%.

Only 1.2% of patients experienced toxicities that required permanent discontinuation of teclistamab. These patients experienced pneumonia and hypercalcemia. Seventy-three percent of patients required dose interruptions.

The toxicities that were most frequently experienced with the agent included pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.

FDA approves teclistimab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. October 25, 2022. Accessed October 25, 2022. https://bit.ly/3f3HffB

Tecvayli. Prescribing information; 2022. Janssen Biotech, Inc. Accessed October 25, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761291s000lbl.pdf

A study of teclistimab, in participants with relapsed or refractory multiple myeloma (MajesTEC-1). Clinicaltrials.gov. Updated October 6, 2022. Accessed October 25, 2022. https://clinicaltrials.gov/ct2/show/NCT04557098

Patients with multiple myeloma who have already undergone 4 lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, may now receive treatment with teclistamab-cqyv (Tecvayli).

Teclistamab-cqyv Snags Accelerated Approval for Relapsed or Refractory Multiple Myeloma

Aggressive screening for financial toxicity and a multidisciplinary intervention for patients with a high financial burden led to improved overall survival (OS) and quality-of-life outcomes for patients with hematologic malignancies, according to findings published in 

The estimated 6-month OS rates were estimated to be 81.4% (95% CI, 68.9%-89.2%) in the interventional cohort (n = 59) and 73.9% (95% CI, 58.7%-84.3%) in the standard care cohort (n = 46). The 12-month estimated OS rates were 73.0% (95% CI, 59.0%-82.9%) and 46.4% (28.9%-63.8%), respectively. In a univariate analysis, the intervention was significantly associated with survival (HR, 0.44; 95% CI, 0.22-0.86; 

 = .017). After adjusting for race, stem cell transplant history, as well as treatment with oral chemotherapy or immunotherapy, the HR was 0.44 (95% CI, 0.21-0.94;

“This study helps to define and characterize [financial toxicity] in treatments of hematologic malignancies,” Thomas Knight, MD, a medical oncologist specializing in hematology at Atrium Health Carolinas, and coinvestigators wrote in the study. “More importantly, these data suggest that screening and intervention is feasible in this population and is associated with improvement in survival and quality of life.”

Financial toxicity is gradually becoming more recognized as a key barrier to cancer care across all tumor types. The term refers to financial issues related to disease burden, much as physical toxicities relate to treatment. Although there is a growing body of research describing the problem, a key focus for investigators should be identifying screening tools and interventions that can be applied in a busy and diverse clinical setting, according to investigators.

This analysis was conducted at Levine Cancer Institute’s leukemia clinic between May 26, 2019, and March 10, 2020. Patients were screened for inclusion via 2 standardized previsit question surveys, the Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 measure and the Comprehensive Score for financial Toxicity (COST). Patients who scored 5 or under were identified as experiencing financial toxicity and flagged for inclusion.

First, investigators identified the degree of financial toxicity. Key stakeholders were identified to assist at several levels of the process, highlighting the need for interdisciplinary team support. Nurse navigators undertook this effort, analyzing demographic data including education level, work history, income, marital status, and family size. Patients were asked questions about delays in care, reasons for delays, and missed medical interventions because of cost.

Pharmacists worked to identify opportunities for cost savings. All medications and co-pays were evaluated by a clinical pharmacist and pharmacy technician. The pharmacy team worked with the prescribing clinician to identify available internal and external grant fundings. They also explored opportunities for more cost-effective treatment strategies if they were unable to decrease medications costs to a manageable level. Cost was calculated into patient-specific dosing decisions.

Social workers evaluated patients to see if they were eligible for any grant funding to assist with co-pays, transportation, or household expenses. If patients qualified, the social worker facilitated the application process and connected them with the funder. Social workers also looked at patient’s insurance status to see if they could help patient obtain appropriate insurance coverage when needed.

Lastly, a financial counselor was used. These were volunteer certified financial planners who worked in the local community and chose to become involved with the project. They were recruited via an email from the Foundation of Financial Planning and given a specific training course on financial planning for patients with cancer. For the purpose of this study, patients met with a counselor for at least 3 visits, however, they were encouraged to pursue a longitudinal relationship and continue to meet as long as needed.

Ultimately, 107 patients were both screened and went through the financial toxicity workflow. Most of these patients had Medicare (40.2%) or private insurance (36.5%), but there were a significant number of patients who had Medicaid (16.8%), self-pay (3.7%), and Veterans Affairs Insurance (2.8%). Most patients (80%) earned less than $60,000 annually. In terms of treatment, 55% (n = 59) had received or were receiving intravenous chemotherapy, 60% (n = 64) had history of oral chemotherapy, 33% (n = 35) immunotherapy, and approximately one-third of patients (n = 41) had undergone hematopoietic stem-cell transplant prior to intervention.

Investigators determined that patients with detectable financial toxicity also had increased rates of medication nonadherence—both with prescription (16.8%) and over-the-counter medications (15.9%). Notably, 17% of patients (n = 18) shared that they missed prescription medications because they could not afford it. Unfortunately, nearly half of patients experiencing financial toxicity reported various coping strategies such as reducing food spending (n = 52) or using savings (n = 55) to cover out-of-pocket expenses. Because of the costs associated with certain cancer therapies, 11% of patients with financial toxicity (n = 5) took a reduced dose of their prescribed medication in an attempt to stretch out their prescriptions.

Primary outcomes were measured by improvements in mental and physical quality of life in all patients as well as improvements in overall survival. Patients who received the financial toxicity intervention not only had improved OS, but also experienced improved quality of life compared with the nonintervention cohort. When measured via the PROMIS analysis changes in physical health scores from baseline were 12.5 ± 2.2 in the interventional cohort vs 13.7 ± 1.8 in the standard care cohort, and the changes in mental health scores from baseline were 11.4 ± 2.2 vs 12.4 ± 2.2, respectively (

According to study authors, the Levine Cancer Clinic is fortunate to be a well-established institution with support systems including nurse navigators, clinical pharmacists, and financial counselors to help patients navigate financial options. Unfortunately, these findings suggest that even more specific screenings and interventions may be required at other institutions, where the lack of support systems could make the effects of financial toxicity more profound.

“Although this is not a randomized control trial and causation cannot be reliably ascertained, there appears to be an associated benefit in both quality of life and mortality with this multimodal approach,” study authors concluded. “The quality-of-life improvement was seen in both the mental and physical domains of the PROMIS Global-10 measure, which may indicate both reduction in the stress that financial strain so often brings but also the improved care that comes with the ability to be compliant.”

They added that the improvement in survival may be liked to increased treatment adherence in the intervention cohort, and that these findings reinforce the need for regressive surveillance and intervention on financial toxicity in this patient population.

Knight TG, Aguiar M, Robinson M, et al. Financial toxicity intervention improves outcomes in patients with hematologic malignancy. 

. 2022;18(9):e1494-e1504. doi:10.1200/OP.22.00056

A multidisciplinary intervention to address financial toxicity led to improved overall survival rates for patients with blood cancers.

Strategies to Combat Financial Toxicity Improve Overall Survival Rates in Patients With Hematologic Malignancies

Deeper and prolonged undetectable minimal residual disease (uMRD) responses were observed in elderly or unfit patients with chronic lymphocytic leukemia (CLL) who received frontline treatment with a fixed dose of ibrutinib (Imbruvica) and venetoclax (Venclexta), according to data from a subgroup analysis of the phase 3 GLOW trial (NCT03462719). According to investigators, this benefit translates to fewer relapses in the first year following treatment cessation.

With 34.1 months of follow-up after treatment completion, the rate of uMRD below 10-4 and 10-5 was significantly higher with ibrutinib/venetoclax (n = 106) compared with chlorambucil/obinutuzumab (n = 105) in the bone marrow and peripheral blood

In the bone marrow, the rate of uMRD was 51.9% (10-4, 11.3%; 10-5, 40.6%) with ibrutinib/venetoclax vs 17.1% (10-4, 9.5%; 10-5, 7.6%) with chlorambucil/obinutuzumab. In the peripheral blood, these rates were 54.7% (10-4, 11.3%; 10-5, 43.4%) and 39.0% (10-4, 21.0%; 10-5, 18.1%), respectively.

“All-oral, once-daily, fixed-duration ibrutinib plus venetoclax achieved deeper and better sustained uMRD responses vs chlorambucil/obinutuzumab as assessed by next-generation sequencing [NGS],” lead study author Talha Munir, MBBS, a consultant hematologist at St James’s Hospital in Leeds, United Kingdom, and coauthors, wrote in the poster presented at the 2022 SOHO Annual Meeting.

In the primary analysis of the GLOW trial, ibrutinib plus venetoclax led to an improvement in independent review committee (IRC)–assessed PFS compared with chlorambucil and obinutuzumab (HR, 0.216; 

 < .0001). MRD status has been associated with PFS following chemoimmunotherapy and fixed-duration therapy with venetoclax and an anti-CD20 antibody. However, the effect of MRD on the activity of ibrutinib and venetoclax is not known.

To that end, investigators evaluated MRD outcomes and association with PFS from the GLOW trial.

The study had enrolled patients with previously untreated CLL who were at least 65 years of age or who were under the age of 65 and had a cumulative illness rating score (CIRS) above 6 or creatinine clearance below 70 mL/min.

A total of 211 patients were randomly assigned to receive 420 mg of ibrutinib daily for 3 cycles prior to receiving ibrutinib plus venetoclax for 12 cycles, or 0.5 mg/kg of chlorambucil on days 1 and 15 for 6 cycles plus 1000 mg of obinutuzumab on days 1, 2, 8, and 15 of cycle 1, and day 1 of cycles 2 through 6.

The primary end point of the trial was IRC-assessed PFS. In the current analysis, MRD was evaluated via NGS with a sensitivity of either 10-4 or 10-5 until 12 months after the end of treatment. Peripheral blood and bone marrow concordance was calculated for patients with uMRD in the peripheral blood 3 months after the end of treatment who had a paired bone marrow sample.

Additional results showed that the uMRD concordance in the bone marrow and peripheral blood below 10-4 was 92.9% for ibrutinib/venetoclax vs 43.6% for chlorambucil/obinutuzumab. At a sensitivity of 10-5, the uMRD concordance was 90.9% and 36.8%, respectively.

In a subgroup analysis, uMRD below 10-4 in the bone marrow favored the use of ibrutinib/venetoclax regardless of age, baseline ECOG performance status, CIRS total score, Rai stage, bulky disease, elevate lactate dehydrogenase, 

Moreover, uMRD in the peripheral blood was better sustained with ibrutinib/venetoclax vs chlorambucil/obinutuzumab from 3 cycles after the end of treatment to 12 cycles after the end of treatment. Specifically, 84.5% (n = 49/58) of patients had uMRD below 10-4 and 80.4% (n = 37/46) had sustained uMRD below 10-5 with ibrutinib/venetoclax vs 29.3% (n = 12/41) and 26.3% (n = 5/19) with chlorambucil/obinutuzumab, respectively.

Only 6% of patients in the ibrutinib/venetoclax arm lost uMRD below 10-4 compared with 27% of those in the chlorambucil/obinutuzumab arm.

“Patients with detectable MRD ≥ 10-4 in the ibrutinib/venetoclax arm were less likely to convert to progressive disease vs those in the chlorambucil/obinutuzumab arm and have worsening of detectable MRD levels,” the study authors wrote.

Further results showed that the PFS rate was better sustained following treatment with ibrutinib/venetoclax vs chlorambucil/obinutuzumab in patients with uMRD below 10-4 in the bone marrow. However, even in patients with detectable MRD of at least 10-4 in the bone marrow or peripheral blood, the PFS rate above 90% was sustained during the first year after treatment completion with ibrutinib/venetoclax, whereas early relapse was common with chlorambucil/obinutuzumab.

Lymph node responses were also generally maintained in patients with uMRD below 10-4 in the bone marrow 3 months after the end of treatment. Additionally, lymph node responses were better maintained over time with ibrutinib/venetoclax compared with chlorambucil/obinutuzumab in patients with detectable MRD of at least 10-4 in bone marrow 3 months after the end of treatment.

“A unique relationship between MRD status and PFS may be explained by broader clearance of multiple disease compartments resulting from complementary mechanisms of ibrutinib and venetoclax,” the study authors concluded. “Additional follow-up is warranted to confirm the longer-term impact of MRD status on PFS.”

Munir T, Moreno C, Owen C, et al. First prospective data on minimal residual disease (MRD) outcomes after fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of CLL in elderly or unfit patients: the GLOW study. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-106

A subgroup of the phase 3 GLOW trial revealed a unique relationship between undetectable minimal residual disease status and progression-free survival in elderly or unfit patients with chronic lymphocytic leukemia who received ibrutinib plus venetoclax. 

Frontline Ibrutinib Plus Venetoclax Reduces Relapse in Elderly Patients with Chronic Lymphocytic Leukemia 

Patients with acute myeloid leukemia (AML) who have undergone bone marrow transplant (BMT) may be at an increased risk of subsequent neoplasms, diabetes, cataracts, venous thromboembolism, or joint replacements, according to findings published in the

. Further, BMT survivors have a history of chronic graft-vs-host-disease (cGVHD), their chance of developing these chronic conditions increases significantly, underscoring the value of close monitoring and multidisciplinary survivorship care in the posttransplant setting.

At 20 years posttransplant, the incidence of severe or life-threatening conditions was 68% among BMT survivors. Compared with their siblings, BMT survivors were significantly more likely to have a grade 3 or 4 chronic health condition (54.9% vs 28.5%) and significantly more likely to have multiple conditions (23.9% vs 7.8%; 

 < .001). Moreover, survivors were more likely to experience poor general health (odds ratio [OR], 3.8; 95% CI, 2.8-5.1), limited activity (OR, 3.7; 95% CI, 3.0-4.5), and functional impairment (OR, 2.9; 95% CI, 2.3-3.6).

“This study provides a global assessment of the burden of morbidity in survivors of AML treated with BMT and finds that, compared with unaffected individuals, BMT survivors are at increased risk for severe/life-threatening health-related complications across nearly all domains,” wrote lead author Saro H. Armenian, pediatric hematologist oncologist and director of the Center for Survivorship and Outcomes with the Hematologic Malignancies Research institute at City of Hope, and co-investigators. “The overall burden of chronic conditions increases sharply with longer follow-up, contributing to a rising incidence of non-relapse mortality.”

Bone marrow transplantation has become a standard treatment for many patients with AML, as it has been established as a curative treatment option. In the United States, the number of patients with AML who undergo a BMT each year is estimated to be around 3,500 and thanks to improvements in transplantation strategies, supportive care, and increased donor source availability, the number of patients with AML continue to increase annually, with more older patients now able to receive this treatment.

It is anticipated that the number of survivors treated with a bone marrow transplant will surpass 40,000 by 2030, thus, ensuring that BMTS survivors are able to live long and healthy lives after their transplant is becoming a critical component of leukemia care.

Previous studies have attempted to characterize the later effects of BMT are generally limited to patients who underwent BMT during their childhood years and were primarily centered on qualities affecting health-related quality of life rather than morbidity. The objective behind this study, therefore, was to understand the associated between BMT-related risk factors and chronic health conditions among BMT recipients, as well as define the overall and cause-specific late mortality rate on survivors throughout various points post-transplant.

Investigators assessed 840 BMT survivors and 1,310 siblings, the mean number of years between BMT and questionnaire completion was 8.2 years. Most patients (86.1%) had undergone allogenic BMT as opposed to autologous BMT. Fifty-two percent of patients had receive a nonmyeloablative or reduced-intensity conditioning. Melphalan- or fludarabine-based regimens were the most popular conditioning (51.0%), followed by a total-body irradiation -based regimen (38.7%).

At 10 years of follow-up, the cumulative incidence of severe, life-threatening, or fatal chronic health conditions was 55% among AML survivors. Specifically, the percentage of patients with subsequent malignant neoplasm was 29.5%, 15.6% developed cataracts, 10.1% required joint replacement, 8.3% experienced venous thromboembolism (8.3%), and 6.8% developed diabetes. Among patients who developed subsequent malignant neoplasm, the most common manifestations included skin cancer or melanoma (68.9%), breast cancer (6.7%), and colon cancer (1.8%).

According to a multivariable, analysis, patients with a history of cGVHD were also more likely to develop grade 3 or worse conditions (HR, 1.3; 95% CI, 1.0-1.6), as well as multiple grade 3 or worse conditions (HR, 2.4; 95% CI, 1.6-3.5).

Moreover, the 5-year survival rate among patients who survived at least 2 years posttransplant was 76.4%. The rate of relapse-related mortality (RRM) was shown to plateau at 30%, although the rate of non-RRM continued to increase, overlapping with RRM at 12 years post BMT and reaching nearly 50% by 30 years posttransplant.

The most common causes of death for those who died in the 2 years following transplant were primary disease (43.8%) and infection (21.3%). In comparison, for 15-year and 20-year survivors, subsequent malignant neoplasm (16.5% vs 21.4%, respectively) and cardiovascular disease (16.5% vs 16.7%, respectively) represented the greatest mortality risks.

“These findings may inform evidence-based health screening recommendations that account for the evolving pattern of morbidity and mortality over time for BMT survivors,” study authors concluded. “These findings support a long-term need for multidisciplinary management of patients with a history of cGVHD, setting the stage for screening, early detection, and interventions to mitigate the risk of adverse health outcomes.”

Armenian SH, Chen Y, Hageman L, et al. Burden of long-term morbidity borne by survivors of acute myeloid leukemia treated with blood or marrow transplantation: the results of the BMT survivor study. 

. 2022;40(28):3278-3288. doi:10.1200/JCO.21.02829

Individuals with AML who underwent a bone marrow transplant are at an increased risk of developing subsequent neoplasms, and other chronic health conditions. 

Later Toxicities Linked to Bone Marrow Transplant Highlight Necessity of Thorough Survivorship Care for Patients With AML 

According to the American Association of Nurse Practitioners, over 36,000 new nurse practitioners (NPs) completed academic programs between 2019 and 2020, and licensed NPs reportedly increased from 325,000 in 2021 to 355,000 in 2022.

As the number of new graduates continues to rise, so will the need for preceptorship, especially in specialties such as oncology.

Preceptors help novices navigate their new role as health care providers, coaching them on such core competencies as diagnostic reasoning, clinical judgment, and critical thinking skills.

 The transition from student to NP can be very difficult, and thus the importance of highly experienced preceptors, particularly in oncology, cannot be overemphasized.

To provide care to oncology patients, NPs need highly specialized training and education, which they usually receive during postgraduate fellowships.

The preceptors’ primary goal is to help the novice bridge educational gaps and advance from entry-level competence to high-level proficiency.

They share knowledge and clinical skills, facilitate experiential learning scenarios, and encourage the development of social, critical thinking, and clinical judgment skills. Preceptors provide this for the novice NP while simultaneously providing safe, high-quality, and holistic care to patients.

Although preceptors are considered to be experts, they still need guidance themselves. According to Pleshkan et al,

 a structured preceptorship improves the process of training a novice NP. Preceptors share their knowledge with the NPs and teach them effective ways to analyze their clinical decisions and manage their workload.

Preceptors must employ the teaching strategies that are best suited to each learner’s style

 and assess the preceptees’ depth of knowledge and level of clinical expertise to facilitate a positive experience.

 In addition, an open dialogue between preceptor and novice gives both the opportunity to become acquainted with one another, clarify goals and expectations, and give/receive constructive feedback. Open dialogue has also been shown to be an effective way to build the preceptor-preceptee relationship and create mutual respect and trust as well as a positive learning environment.

Emotional Support and the Preceptorship Experience

Transitioning from new graduate to proficient NP in any specialty takes time and determination as the process can be intimidating and, at times, anxiety-inducing.

 However, having a guide who has been through the same process can make the transition a healthy and pleasant experience.5 Preceptors ensure the competence of novices. From them novices learn to provide safe, cost-effective care to patients with complex diseases.

What may at first seem like a daunting journey becomes less so thanks to the preceptor’s ongoing reassurance. Preceptors are like personal coaches: they teach learners what to do and offer emotional support throughout.

As I transition from an experienced RN to a novice oncology NP, I see that preceptors have been a critical part of my personal and professional growth. Although most preceptorships are short and not all encounters are positive, many of the connections are genuine. Several of my past preceptors have become lifelong friends and continue to be mentors of mine. Because of their willingness to share their knowledge and clinical expertise, I am confident that when my turn comes, I will be able to pass on what they taught me (plus some tips and tricks of my own) to the next generation.

Novice oncology NPs require a great deal of support as they transition to their new role.

 A structured preceptorship that caters specifically to them promotes a safe environment that is conducive to learning, builds competence, confidence, and job satisfaction and encourages intra- and interdisciplinary collaboration.

 To novice oncology NPs starting their journey in clinical practice, I say that to succeed, you must pay attention, ask questions, and maintain a flexible and positive attitude.

1. NP fact sheet. American Association of Nurse Practitioners. Updated April 2022. Accessed July 15, 2022. https://www.aanp.org/about/all-about-nps/np-fact-sheet

2. Pleshkan V, Boykins AD. Cognitive preceptorship: an emerging nurse practitioner role transition to practice model. 

.2022;39:194-205. doi:10.1016/j.profnurs.2022.02.002

3. Pleshkan V, Hussey, L. Nurse practitioners’ experience with role transition: supporting the learning curve through preceptorship. 

4. Bazzell AF, Jones T, Dains JE, Champion JD. Assessing the needs of oncology APRN preceptors. 

5. Pirschel C. Competencies create expert, accountable nurses delivering quality care. 

.April 3, 2017. Accessed July 15, 2022. https://voice.ons.org/news-and-views/core-competencies-of-oncology-nurses

6. Alencar M, Butler E, MacIntyre J, Wempe EP. Nurse practitioner fellowship: developing a program to address gaps in practice. 

7. Pearson T, Hensley T. Positive precepting: identifying NP student learning levels and needs. 

8. Thomassen A. Fellowship programs: reflections of an advanced practice nurse fellow. 

9. Kelly DE. Initiation of a new nurse preceptor program in the era of COVID-19. 

10. Bazzell AF, Dains JE. Supporting nurse practitioner preceptor development. 

Structured preceptorships promote competence, confidence, and job satisfaction in new oncology nurse practitioners. 

Supporting the Novice Oncology NP: The Benefits of Preceptorship

Findings from 2 clinical trials showed that treatment with rusfertide (PTG-300) helped patients with polycythemia keep their hematocrit levels under 45% and significantly reduced their need for period therapeutic phlebotomies, according to a presentation from the Society of Hematologic Oncology Annual Meeting (SOHO).

Lead study author Naveen Pemmaraju, MD, an associate professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, provided the update.

Currently, there are few treatment options for patients with PV that can help to control hematocrit levels and reduce the need for phlebotomy and the incidence of thrombosis.

Rusfertide is an injectable synthetic mimetic of hepcidin, a natural hormone, that is currently in clinical development as a noncytoreductive treatment option for PV. Hepcidin regulates iron absorption, distribution, and storage, controlling the body’s production of red blood cells. The synthetic agent is suggested to offer greater potency, stability, and solubility than with the natural hormone.

In June 2021, the FDA granted the agent a breakthrough therapy designation as a treatment option for patients with PV.

The agent has been investigated in several clinical trials of patients with PV, including 2 phase 2 studies: REVIVE (NCT04057040) and PACIFIC (NCT04767802). These 2 clinical trials were placed on a clinical hold by the FDA in September 2021 after the identification of a nonclinical finding in a 26-week rasH2 transgenic mouse model study showing benign and malignant subcutaneous skin tumors.

 The full clinical was then lifted in October 2021 following a review by the FDA. New safety and stopping rules were added to the study protocols for the protection of patients in the ongoing studies. No other unexpected safety signals were reported during the review.

The REVIVE study is a randomized phase 2 trial of patients with PV requiring phlebotomy consisting of 3 parts: a 28-week open-label dose-escalation phase in which the dose of rusfertide is titrated until hematocrit levels below 45% can be achieved; a 12-week blinded, randomized, withdrawal phase in which patients receive rusfertide or placebo; and an open-label extension lasting up to 3 years. Treatment was administered subcutaneously at doses between 10 mg and 120 mg weekly.

About 80 patients were enrolled in the trial. Patients were allowed to still be receiving cytoreductive therapy or hydroxyurea, interferon, or ruxolitinib (Jakafi) as long as they were on a relatively stable dose of therapy. Those with post-PV myelofibrosis or known immunodeficiency were excluded from the study.

The primary end point was the proportion of responders during the blinded, randomized, withdrawal portion of the trial. Secondary end points included the change in phlebotomy requirements and the number of patients achieving a response by week 29.

PACIFIC is an open-label, single-arm phase 2 trial of patients with PV and elevated hematocrit levels of about 48% where current therapies cannot control these levels. The study took place in 2 parts: an induction phase, in which patients received induction with 40-mg subcutaneous rusfertide twice weekly until hematocrit levels dipped below 45%, and a continuation phase with weekly dosing of rusfertide, with treatment lasting up to 52 weeks.

Approximately 20 patients were enrolled in the study who had all other causes of erythrocytosis ruled out. Those with clinically significant thrombosis, post-PV myelofibrosis, infection, immunodeficiency, active hepatitis or HIV, or a history of invasive malignancy were excluded from the study.

The trial sought to determine the safety and efficacy of rusfertide.

Pemmaraju will provide an update to findings, which has showed that patients were mostly able to be without phlebotomy and maintain hematocrit levels below 45% in the REVIVE study. Additionally, ferritin levels normalized with the use of rusfertide. In the PACIFIC study, hematocrit levels under 45% were maintained for about 6 weeks.

When dosing stopped in both studies with the clinical hold, patients required phlebotomy again, hematocrit levels increased, red blood cell counts rose, and serum ferritin levels dropped. After the hold was lifted, levels normalized and patients no longer required phlebotomy once again.

These data provide support for the ongoing, randomized phase 3 VERIFY trial (NCT05210790), which intends to enroll about 250 patients with PV who require frequent phlebotomy. In the first part of the study, patients will be randomly assigned in a blinded fashion to receive either rusfertide or placebo plus standard therapy for 32 weeks. The second part is an open-label phase where rusfertide treatment is ongoing for 124 weeks.

The primary end point is patients achieving a response and secondary end points include changes in phlebotomy, total fatigue scores, and myelofibrosis symptoms.

Pemmaraju N, Kuykendall A, Kremyanskaya M, et al. Rusfertide (PTG-300) treatment interruption reverses hematological gains and upon reinitiation, restoration of clinical benefit observed in patients with polycythemia vera. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Abstract MPN-469.

Product candidates: rusfertide (PTG-300). Protagonist Therapeutics. Accessed September 8, 2022. https://bit.ly/3ihxucZ

Protagonist Therapeutics receives FDA breakthrough therapy designation for rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 3, 2021. Accessed September 8, 2022. https://bit.ly/3vRx6Gd

Protagonist Therapeutics reports FDA clinical hold on rusfertide clinical development program. News release. Protagonist Therapeutics. September 17, 2021. Accessed September 8, 2022. https://bit.ly/3iUiLUY

Protagonist Therapeutics announces removal of FDA clinical hold on the rusfertide clinical development program. News release. Protagonist Therapeutics. October 11, 2021. Accessed September 8, 2022. https://bit.ly/2YF5nge

Following treatment with rusfertide, patients with polycythemia vera were able to significantly reduce their need for blood draws. 


Rusfertide Leads to Controlled Hematocrit Levels and Fewer Phlebotomies in Polycythemia Vera 

As the cancer treatment landscape continues to evolve, the role of front-line nurses in clinical trials remains essential, according to Anne Delengowski, RN, MSN, AOCN, CCCTM.

“I don’t know if nurses today can truly appreciate where we’ve come because they were never there, [but] I have had the honor and privilege of being there,” Delengowski, who has been an oncology nurse for 42 years, and is the director of Oncology Nursing Education at Thomas Jefferson University Hospital, said in an interview. “In the past, we had very few cancer drugs, we had minimal second-line therapies which are standard now, we didn’t have targeted therapy or immunotherapy, and we had poor symptom management.” 

Delengowski recently presented at the 2022 Oncology Nursing Society Bridge, highlighting notable improvements spanning the course of her career and the excitement that comes with being a part of a clinical trial from start to finish. In a post-presentation interview with 

®, Delengowski offered a personal perspective into how the field has changed during her career as a frontline nurse.

“When I first started as a cancer nurse, we didn’t have the antiemetics we have today, and it was awful. I did a study back then with a colleague from the school of nursing looking at anticipatory nausea and vomiting because the patients would come in vomiting prior to getting their drugs because they were anticipating it happening, [but] very rarely do you see that anymore. We [also] didn’t have growth factors; we didn’t have the colony stimulators to be able to prevent neutropenic fevers, so patients were hospitalized for most of the course of their disease. Today, all the stuff we talked about here came through clinical trials.”

She also highlighted how pain management strategies have significantly improved.

“I worked a lot in nightshift when I was in graduate school, and we didn’t have sustained release narcotics,” she said. “We used to have to wake people up in the middle of the night to give them pain medicine because if we didn’t their pain would be out of control in the morning. Once again, it was revolutionized that we have PCA [patient-controlled analgesia] pumps now, we have sustained release therapy. The nightmare of seeing patients in pain, you kind of weighed the fact if I didn’t wake them up, they’d be in a lot of pain in the morning and if I did wake them up, I interrupted their sleep, and it wasn’t good.”

Throughout her career, she shared that she has been inspired by the advances that clinical trials have brought about. She noted that patients are living longer, healthier lives, and that clinical trials are allowing providers to achieve “magical things.”

She noted, as an example, the breakthrough findings from Memorial Sloan Kettering Cancer Center where 100% of patients with rectal mismatch repair-deficient locally advanced rectal cancer achieved a complete response with dostarlimab-gxly (Jemperli).

Delengowski shared that, prior to working in clinical trials, she did not understand much about the process or have proper understanding or the extent of the behind-the-scenes work. For example, in her presentation, she explained how clinical trials must receive approval form a multidisciplinary disease group and a facilitation committee, along with a protocol review committee. In addition, there is a site initiation visit which provides the principal investigator and the team with training on all aspects of the trial, prior to its initiation.

Teamwork is also critical and research coordinators who understand the trial have been involved from the inception to guide nurses.

As part of her presentation, Delengowski outlined the different phases of clinical trials. Phase 1 trials are specifically designed to find a safe dose of a novel regimen for humans. This step determines how much a new treatment should be given (ie, oral or intravenous administration), and what the maximum-tolerated dose is.

Delengowski stressed, “A lot of times in phase 1 [trials] we don’t know what the symptoms or outcomes might be, so we need to be cognizant of the fact that anything that happens to that patient we need to document. We need to make sure we do it and we need to follow the protocol to dot the i, cross the t and do it all perfectly because if everyone chooses to do something different than it really doesn't make the trial valuable.”

“I remember giving my very first phase 1 [treatment] and I took a step back thinking ‘You want me to give this to a human being now? It’s the first time a human being has received this drug,’” she said. “I was humbled and wowed at the same time. It was wonderful for all involved, but a little frightening it was for us [as nurses] to administer.”

Phase 2 trials are larger and are designed to determine if the new treatment is effective against a certain cancer, as well as its safety profile. Phase 3 trials compare the new treatment (or new use of a treatment) against the current standard of care.

Across the trial continuum, supporting patients during the trial remains a significant part of the nurse’s role as patients can be overwhelmed throughout treatment. Delengowski highlighted that knowing where to get information for patients and helping to educate them is important for front-line nurses.

“It becomes very exciting when you know you’re part of [clinical trials],” she said. “Some frontline nurses may not exactly understand the value they bring, but [they’re] invaluable; We’re the frontline, we’re the last line, we’re the point where the person gets the medication or the therapy.”

However, phase 3 trials, which are usually randomized, can be difficult for nurses, because patients may not be happy to learn they were randomly assigned to receive the standard of care.

Delengowski explained “It's very hard when you talk up a study and the patient was randomized to standard of care. Often a frontline nurse will be confronted with [patients who say] ‘I signed on thinking I was going to get the new therapy and now I got standard of care drug.’ ”

“What I tell [patients] is in phase 3 studies we don’t know that standard care might be the best therapy. We don’t know and that’s what this is all about. I’ve been involved in phase 3 [trials], where the [experimental drug] was not better than standard of care; it was good, but not as good. It’s just part of the process and once you give that information to the patient, they feel a bit better about it.”

When looking back on all the various phases of clinical trials she has been a part of, Delengowski said it was an exciting feeling to think, “Wow, I was part of that, and we were there when it happened. Some of the trials didn’t come to fruition, but a lot of them did and when you look at that and know that you were part of it, it is so exciting…. As cancer nurses we see the patient go through from diagnosis to hopefully a long life, but in between there’s roadblocks. If they fail first-line therapy and other therapies and go onto a clinical trial, we walk that walk with them. I think that understanding that there is that next step [is important].”

Future steps in improving the clinical trial process include ensuring that inclusivity is a priority and that trials will be brought to the community. Historically, clinical trials have been performed in large academic centers which can be difficult to get to and exploring ways to bring them to patients and working with a community-based staff can be beneficial in making the clinical trials more comfortable for patients.

“[Clinical trials] give that glimmer of hope to someone that there may be other outcomes out there,” Delengowski said. “Even if it’s not something that’s going to be beneficial for that individual, which is not always the case, but it leads to phase 2 and phase 3 [trials] where there seemingly is some hope for a disease process that might not have had a whole lot of other options.”

Delengowski A. Clinical trials on the frontline: the changing landscape of clinical trials nursing. Presented at: ONS Bridge; September 13-15, 2022; virtual.

Cercek A, Lumish MA, Sinopoli JC, et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. 

. 2022;40(suppl 17):LBA5. doi:10.1200/JCO.2022.40.17_suppl.LBA5

Anne Delengowski, RN, MSN, AOCN, CCCTM, discusses the evolving role of the oncology nurse in clinical trial research.

Hematology