Mantle Cell Lymphoma

Given the patient's diagnosis of stage IV MCL, the presentation of diffuse skin lesions, and the histopathologic and immunophenotyping results of those lesions, this patient is diagnosed with secondary cutaneous MCL. The hematologist-oncologist discusses the findings with the patient and presents potential next steps and treatment options. 

MCL is a type of B-cell neoplasm that, with advancements in the understanding of non-Hodgkin lymphoma (NHL) in the past 30 years, has been defined as its own clinicopathologic entity by the Revised European-American Lymphoma and World Health Organization classifications. Up to 10% of all NHLs are MCL. Clinical presentation includes advanced disease with B symptoms (eg, night sweats, fever, weight loss), generalized lymphadenopathy, abdominal distention associated with hepatosplenomegaly, and fatigue. Skin manifestations are not as common as other extranodal manifestations. Primary cutaneous MCL occurs in up to 6% of patients with MCL; secondary cutaneous involvement is slightly more common, occurring in 17% of patients with MCL. Secondary cutaneous MCL usually presents in late-stage disease. Men are more likely to present with MCL than are women by a ratio of 3:1. Median age at presentation is 67 years. 
 
Diagnosing MCL is a multipronged approach. Physical examination may reveal lymphadenopathy and hepatosplenomegaly. Lymph node biopsy and aspiration with immunophenotyping in MCL reveals monoclonal B cells expressing surface immunoglobulin (Ig), IgM, or IgD, that are characteristically CD5+ and pan B-cell antigen–positive (eg, CD19, CD20, CD22) but lack expression of CD10 and CD23 and overexpress cyclin D1. Bone marrow aspirate/biopsy are used more for staging than for diagnosis. Blood studies, including anemia and cytopenias secondary to bone marrow infiltration (with up to 40% of cases showing lymphocytosis > 4000/μL), abnormal liver function tests, and a negative Coombs test also help diagnose MCL. Secondary cutaneous MCL is diagnosed on the basis of an MCL diagnosis along with diffuse infiltration of the skin, with multiple erythematous papules and nodules coalescing to form plaques; skin biopsy and immunohistopathology showing monotonous proliferation of small- to medium-sized lymphoid cells with scant cytoplasm; irregular cleaved nuclei with coarse chromatin; and inconspicuous nucleoli as well as a spared papillary dermis.

Pathogenesis of MCL involves disordered lymphoproliferation in a subset of naive pregerminal center cells in primary follicles or in the mantle region of secondary follicles. Most cases are linked with translocation of chromosome 14 and 11, which induces overexpression of protein cyclin D1. Viral infection (Epstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpes virus 6), environmental factors, and primary and secondary immunodeficiency are also associated with the development of NHL.

Patient education should include detailed information about clinical trials, available treatment options, and associated adverse events as well as psychosocial and nutrition counseling. 

Chemoimmunotherapy is standard initial treatment for MCL, but relapse is expected. Chemotherapy-free regimens with biologic targets, which were once used in second-line treatment, have increasingly become an important first-line treatment given their efficacy in the relapsed/refractory setting. Chimeric antigen receptor T-cell therapy is also a second-line treatment option. In patients with MCL and a TP53 mutation, clinical trial participation is encouraged because of poor prognosis.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grants from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Given the patient's diagnosis of stage IV MCL, the presentation of diffuse skin lesions, and the histopathologic and immunophenotyping results of those lesions, this patient is diagnosed with secondary cutaneous MCL. The hematologist-oncologist discusses the findings with the patient and presents potential next steps and treatment options. 

MCL is a type of B-cell neoplasm that, with advancements in the understanding of non-Hodgkin lymphoma (NHL) in the past 30 years, has been defined as its own clinicopathologic entity by the Revised European-American Lymphoma and World Health Organization classifications. Up to 10% of all NHLs are MCL. Clinical presentation includes advanced disease with B symptoms (eg, night sweats, fever, weight loss), generalized lymphadenopathy, abdominal distention associated with hepatosplenomegaly, and fatigue. Skin manifestations are not as common as other extranodal manifestations. Primary cutaneous MCL occurs in up to 6% of patients with MCL; secondary cutaneous involvement is slightly more common, occurring in 17% of patients with MCL. Secondary cutaneous MCL usually presents in late-stage disease. Men are more likely to present with MCL than are women by a ratio of 3:1. Median age at presentation is 67 years. 
 
Diagnosing MCL is a multipronged approach. Physical examination may reveal lymphadenopathy and hepatosplenomegaly. Lymph node biopsy and aspiration with immunophenotyping in MCL reveals monoclonal B cells expressing surface immunoglobulin (Ig), IgM, or IgD, that are characteristically CD5+ and pan B-cell antigen–positive (eg, CD19, CD20, CD22) but lack expression of CD10 and CD23 and overexpress cyclin D1. Bone marrow aspirate/biopsy are used more for staging than for diagnosis. Blood studies, including anemia and cytopenias secondary to bone marrow infiltration (with up to 40% of cases showing lymphocytosis > 4000/μL), abnormal liver function tests, and a negative Coombs test also help diagnose MCL. Secondary cutaneous MCL is diagnosed on the basis of an MCL diagnosis along with diffuse infiltration of the skin, with multiple erythematous papules and nodules coalescing to form plaques; skin biopsy and immunohistopathology showing monotonous proliferation of small- to medium-sized lymphoid cells with scant cytoplasm; irregular cleaved nuclei with coarse chromatin; and inconspicuous nucleoli as well as a spared papillary dermis.

Pathogenesis of MCL involves disordered lymphoproliferation in a subset of naive pregerminal center cells in primary follicles or in the mantle region of secondary follicles. Most cases are linked with translocation of chromosome 14 and 11, which induces overexpression of protein cyclin D1. Viral infection (Epstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpes virus 6), environmental factors, and primary and secondary immunodeficiency are also associated with the development of NHL.

Patient education should include detailed information about clinical trials, available treatment options, and associated adverse events as well as psychosocial and nutrition counseling. 

Chemoimmunotherapy is standard initial treatment for MCL, but relapse is expected. Chemotherapy-free regimens with biologic targets, which were once used in second-line treatment, have increasingly become an important first-line treatment given their efficacy in the relapsed/refractory setting. Chimeric antigen receptor T-cell therapy is also a second-line treatment option. In patients with MCL and a TP53 mutation, clinical trial participation is encouraged because of poor prognosis.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grants from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Given the patient's diagnosis of stage IV MCL, the presentation of diffuse skin lesions, and the histopathologic and immunophenotyping results of those lesions, this patient is diagnosed with secondary cutaneous MCL. The hematologist-oncologist discusses the findings with the patient and presents potential next steps and treatment options. 

MCL is a type of B-cell neoplasm that, with advancements in the understanding of non-Hodgkin lymphoma (NHL) in the past 30 years, has been defined as its own clinicopathologic entity by the Revised European-American Lymphoma and World Health Organization classifications. Up to 10% of all NHLs are MCL. Clinical presentation includes advanced disease with B symptoms (eg, night sweats, fever, weight loss), generalized lymphadenopathy, abdominal distention associated with hepatosplenomegaly, and fatigue. Skin manifestations are not as common as other extranodal manifestations. Primary cutaneous MCL occurs in up to 6% of patients with MCL; secondary cutaneous involvement is slightly more common, occurring in 17% of patients with MCL. Secondary cutaneous MCL usually presents in late-stage disease. Men are more likely to present with MCL than are women by a ratio of 3:1. Median age at presentation is 67 years. 
 
Diagnosing MCL is a multipronged approach. Physical examination may reveal lymphadenopathy and hepatosplenomegaly. Lymph node biopsy and aspiration with immunophenotyping in MCL reveals monoclonal B cells expressing surface immunoglobulin (Ig), IgM, or IgD, that are characteristically CD5+ and pan B-cell antigen–positive (eg, CD19, CD20, CD22) but lack expression of CD10 and CD23 and overexpress cyclin D1. Bone marrow aspirate/biopsy are used more for staging than for diagnosis. Blood studies, including anemia and cytopenias secondary to bone marrow infiltration (with up to 40% of cases showing lymphocytosis > 4000/μL), abnormal liver function tests, and a negative Coombs test also help diagnose MCL. Secondary cutaneous MCL is diagnosed on the basis of an MCL diagnosis along with diffuse infiltration of the skin, with multiple erythematous papules and nodules coalescing to form plaques; skin biopsy and immunohistopathology showing monotonous proliferation of small- to medium-sized lymphoid cells with scant cytoplasm; irregular cleaved nuclei with coarse chromatin; and inconspicuous nucleoli as well as a spared papillary dermis.

Pathogenesis of MCL involves disordered lymphoproliferation in a subset of naive pregerminal center cells in primary follicles or in the mantle region of secondary follicles. Most cases are linked with translocation of chromosome 14 and 11, which induces overexpression of protein cyclin D1. Viral infection (Epstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpes virus 6), environmental factors, and primary and secondary immunodeficiency are also associated with the development of NHL.

Patient education should include detailed information about clinical trials, available treatment options, and associated adverse events as well as psychosocial and nutrition counseling. 

Chemoimmunotherapy is standard initial treatment for MCL, but relapse is expected. Chemotherapy-free regimens with biologic targets, which were once used in second-line treatment, have increasingly become an important first-line treatment given their efficacy in the relapsed/refractory setting. Chimeric antigen receptor T-cell therapy is also a second-line treatment option. In patients with MCL and a TP53 mutation, clinical trial participation is encouraged because of poor prognosis.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grants from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The European Society for Medical Oncology (ESMO), in collaboration with the European Hematology Association, has released a tool to help hematologists evaluate the magnitude of clinical benefit expected from new blood cancer treatments.

It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.

Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.

On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.

The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.

The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.

To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.

Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.

The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.

ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.

The European Society for Medical Oncology (ESMO), in collaboration with the European Hematology Association, has released a tool to help hematologists evaluate the magnitude of clinical benefit expected from new blood cancer treatments.

It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.

Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.

On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.

The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.

The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.

To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.

Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.

The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.

ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.

The European Society for Medical Oncology (ESMO), in collaboration with the European Hematology Association, has released a tool to help hematologists evaluate the magnitude of clinical benefit expected from new blood cancer treatments.

It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.

Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.

On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.

The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.

The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.

To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.

Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.

The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.

ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

Background 

Of the approximately 80,000 individuals diagnosed annually in the United States with a non-Hodgkin lymphoma (NHL), MCL accounts for an estimated 5%.^1,2 At the time of diagnosis, most of these patients have advanced disease. The diagnosis of MCL is made based on characteristic immunophenotype and the presence of (11;14)(q13;q32) translocation resulting in overexpression of cyclin D1.^3,4 Long-term survival has been observed in a small proportion of patients with MCL, but this disease is generally considered incurable.⁵

Except for the approximately 10% of patients with MCL who present with asymptomatic indolent disease, for whom a watch-and-wait approach is generally used,⁶ there are 2 types of treatment strategies. One is applied to people who are fit and relatively young. In these cases, intensive chemotherapy with or without ASCT has been the dominant approach. In patients who are poor candidates for the toxicities associated with aggressive treatment, less intensive approaches are applied. These strategies include not only better-tolerated combinations of cytotoxic chemotherapies, but also various combinations that involve immunomodulators or small molecule enzyme inhibitors. Although less toxic, these regimens are active, often achieving a complete response (CR) and an extended progression-free survival (PFS).³

These 2 pathways of MCL treatment are reflected in guidelines from the National Comprehensive Cancer Network (NCCN), which describe separate first-line algorithms for stage I and stage II non-bulky disease and stage II bulky and advanced stage disease.⁷ For stage II bulky or advanced stage disease, separate pathways are described for indolent, TP53-mutated, and TP53 wild-type MCL and are further divided into pathways for those who are candidates for ASCT and those who are not.

Currently, “chemotherapy-free” therapies, a term that is sometimes used to identify drug combinations with modest or no cytotoxic effects, though inaccurate, are not preferred for first-line therapy in any group in the NCCN guidelines. However, immunomodulators, such as lenalidomide and targeted therapies, such as Bruton tyrosine kinase inhibitors (BTKis) are being actively tested in the front-line setting with promising results. Practical approaches to the application of these agents are described in trials presented or published in the last year, including TRIANGLE and SHINE.^10,11

Rethinking Front-Line MCL Therapy in the Young and Fit

Case Study

A 52-year-old man with a history of smoking presented with shortness of breath and general fatigue. The medical history included no major chronic diseases. The patient, who was referred after a routine examination, reported a recent decrease in body weight of unknown cause. Enlargement of inguinal, axillary, and submaxillary lymph nodes on examination along with laboratory abnormalities, such as anemia, and elevated lymphoid cells in the peripheral blood, raised suspicion of a lymphoproliferative disorder. A diagnosis of MCL was reached based on characteristic lymphoid cell morphology and immunotyping positive for CCND1 on lymph node biopsy. Ki-67 was 50% with wild-type TP53 on next-generation sequencing. The disease was characterized as stage III with intermediate risk MIPI (Mantle Cell Lymphoma International Prognostic Index).

For this presentation, one NCCN-guideline recommendation is a cytarabine-containing intensive chemotherapy regimen with rituximab followed by ASCT with maintenance rituximab in patients who are fit for transplant,⁷ but the recent data from the multicenter open-label TRIANGLE study has challenged this paradigm.¹⁰

In TRIANGLE, 870 treatment-naïve patients younger than age 65 (median age 57 years) were randomized to 1 of 3 study arms.¹⁰ In the control arm, patients received the standard-of-care induction with intensive chemoimmunotherapy (CIT) with ASCT consolidation (CIT + ASCT). In 1 of 2 experimental arms, patients received CIT + ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance (CIT + I + ASCT). In the other experimental arm, patients received CIT + ibrutinib followed by 2 years of ibrutinib maintenance with ASCT omitted (CIT + I). Rituximab maintenance as a single dose administered every 2 months for up to 3 years was permitted in all arms.

Most (87%) of the patients in TRIANGLE had stage IV disease and most (85%) had low- or intermediate-risk MIPI. The primary endpoint was failure-free survival (FFS). Rates of FFS at 3 years were 72% for the CIT+ ASCT arm, 88% for the CIT + I + ASCT arm, and 86% for the CIT + I arm. Overall survival (OS) at 3 years, during which time the trial was amended to permit rituximab maintenance in all 3 study arms, numerically favored ibrutinib arms (92% for CIT + I and 91% for CIT + I + ASCT), over chemotherapy alone (86% for CIT + ASCT).

The TRIANGLE trial does not yet establish a new standard for the types of patients enrolled, but it does show clearly that the use of ibrutinib with CIT was not inferior to the standard intensive approach integrating ASCT, and most types of adverse events occurred with less frequency in the ibrutinib-only arm.

There are numerous questions to pose and a broader understanding of applicability to be gained as more follow-up of this study and other studies utilizing targeted therapies, including other BTK inhibitors, provide mor data. Of particular interest is whether the presence of minimal residual disease (MRD) and the prognostic implications of MRD are affected by the use of a BTKi and/or ASCT. The E4151 and E4181 clinical trials may collectively provide greater insight here.^12,13

Rethinking Front-Line MCL Therapy in Older Patients

Case Study

A 74-year-old man with a history of cardiovascular disease, including a prior ST-elevated myocardial infarction, presents with nonspecific symptoms, including night sweats, intermittent fevers, and fatigue. Despite his symptoms, he continues to work 3 days per week and participates in a weekly game of doubles tennis. Axillary swelling leads him to seek medical attention. Imaging demonstrates diffuse lymphadenopathy. An axillary lymph node biopsy confirms a diagnosis of MC with FISH (fluorescence in situ hybridization) positive for t(11;14). He is of intermediate risk on MIPI scoring.

Due to his age and concurrent heart disease, he is not a candidate for aggressive chemotherapy and ASCT. Less aggressive therapies including bendamustine plus rituximab (BR),^14,15 lenalidomide plus rituximab (RR),⁸ and rituximab, bendamustine, and cytarabine (R-BAC) are discussed with this patient.¹⁶

Based on STiL data and BRIGHT studies, BR has become a widely used regimen.^14,15 However, attempts are being made to improve upon the BR backbone with the addition of BTK inhibitors.¹¹ In SHINE, BR plus ibrutinib further improved PFS relative to BR alone. SHINE was a 2-arm study, which was restricted to patients 65 years of age or older (median age 71 years); 523 previously untreated patients with good performance status and acceptable organ function were randomized to BR or BR plus ibrutinib. Most patients had intermediate- (~48%) or high- (~34%) risk MIPI. More than 90% had advanced-stage disease. Of patients in whom the TP53 mutation status was established, only about 10% were positive.

In the arm receiving BR alone, the median PFS was 52.9 months. With the addition of 560 mg once-daily ibrutinib to 6 cycles of BR followed by maintenance rituximab and continued ibrutinib, the median PFS, which was the primary endpoint, climbed to a median of 80.6 months. BR plus ibrutini was associated with a 41% reduction in the hazard ratio (HR) for progression or death (HR 0.75; P=.01). When stratified by risk factors, the advantage of BR plus ibrutinib was particularly pronounced in patients with intermediate-risk, (although not high-risk) nonmutated TP53, and less bulky disease.¹¹

There was no significant effect of the addition of ibrutinib on OS at the last analysis, but the longer PFS was achieved with only a modest increase in adverse events (AEs). For AEs of grade 3 or higher, the AE rates for BR plus ibrutinib and BR alone were 81.5% and 77.3%, respectively. Rates of cytopenias, including grade 3 or higher, were similar in the 2 arms. Rash and gastrointestinal AEs, such as diarrhea, nausea, and abdominal pain, occurred more frequently among patients who received ibrutinib.¹¹

Without an OS advantage, the SHINE trial does not establish a new standard of care, particularly given that it was voluntarily revoked from the market for the treatment of MCL. However, results are likely to accelerate interest in evaluating other targeted therapies, in combination with other relatively well-tolerated treatments. In patients with MCL unfit for ASCT, there is interest in pursuing other BTK inhibitors, particularly with ibrutinib being revoked as an indication for MCL. including the newer noncovalent pirtobrutinib, which was recently approved for MCL in the relapsed/refractory setting,¹⁷ and bispecific T-cell engagers (BiTEs) such as glofitamab.¹⁸

Rethinking Front-Line in TP53-Mutated MCL

Case Study

A previously healthy 62-year-old woman who presents with rapidly progressing lymphadenopathy and constitutional symptoms is diagnosed with MCL that has multiple adverse features. She has a Ki-67 level higher than 30%, a TP53 mutation, and blastoid morphology.¹⁹

The NCCN guidelines strongly recommend a clinical trial for patients with a TP53 mutation.⁷ Despite various high-intensity combinations to control disease in these patients, the 2017 pooled analysis demonstrated that most patients with TP53 mutations have a poor or no response to chemotherapy with a high side effect burden.¹⁹ In particular, such patients derive little benefit from high-intensity chemotherapy using ASCT.¹⁹

Nonetheless, for TP53-mutated MCL, several regimens have demonstrated activity. Most of these have used highly targeted therapies that offer the potential for low relative rates of toxicity. Two “chemotherapy-free” combinations involving venetoclax, the CD20-targeted obinutuzumab, and BTK inhibitors have completed phase 2 trials with promising results.^20,21 In a study evaluating the BOVen regimen (the second-generation BTK inhibitor zanubrutinib, obinutuzumab, and venetoclax) as time-limited therapy in TP53-mutated patients, 89% of patients achieved MRD at 26 months of follow-up.²⁰

Several novel therapies being tested in the relapsed/refractory setting have generated interest for evaluation in front-line clinical studies. These strategies include the BiTE glofitamab,¹⁸ the antibody-drug conjugate zilovertamab vedotin,²² and the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (brexu-cel).²³ Brexu-cel is already approved in relapsed/refractory MCL.²³ Given the poor response to available treatments seen in patients with TP53 mutations, these novel therapies have the potential to improve outcomes in this population of high unmet need.

Summary

Durable remissions of MCL can be achieved with aggressive combinations of chemotherapy, but recent studies suggest a momentum away from cytotoxic drugs toward therapies with more targeted effects. In at least some patient populations, these therapies can rival the degree and duration of disease control achieved with less well-tolerated treatment. If ongoing trials corroborate the long-term efficacy and safety of these approaches, these therapies may represent an important evolution in MCL management.

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.

Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.

A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.

In the randomized controlled RESTORE study, use of the cell phone–based CBSM app was associated with significantly greater reduction in symptoms of anxiety and depression compared with a digital health education control app.

In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).

However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.

The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.

“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.

“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
 

Impressive and elegant

“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.

“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.

CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.

To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.

Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.

They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
 

High-quality control

Ms. Ramiller said that the control app set “a high bar.”

“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.

A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.

The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).

CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)

An extension study of the durability of the effects at 3 and 6 months is underway.

The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.

“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”

The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
 

A version of this article originally appeared on Medscape.com.

CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.

Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.

A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.

In the randomized controlled RESTORE study, use of the cell phone–based CBSM app was associated with significantly greater reduction in symptoms of anxiety and depression compared with a digital health education control app.

In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).

However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.

The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.

“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.

“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
 

Impressive and elegant

“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.

“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.

CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.

To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.

Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.

They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
 

High-quality control

Ms. Ramiller said that the control app set “a high bar.”

“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.

A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.

The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).

CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)

An extension study of the durability of the effects at 3 and 6 months is underway.

The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.

“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”

The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
 

A version of this article originally appeared on Medscape.com.

CHICAGO – One-third of patients with cancer also experience anxiety or depression, and an estimated 70% of the 18 million patients with cancer and cancer survivors in the US experience emotional symptoms, including fear of recurrence.

Despite many having these symptoms, few patients with cancer have access to psycho-oncologic support.

A digital cognitive-behavioral stress management (CBSM) application may help to ease some of the burden, reported Allison Ramiller, MPH, of Blue Note Therapeutics in San Francisco, which developed the app version of the program.

In the randomized controlled RESTORE study, use of the cell phone–based CBSM app was associated with significantly greater reduction in symptoms of anxiety and depression compared with a digital health education control app.

In addition, patients assigned to the CBSM app were twice as likely as control persons to report that their symptoms were “much” or “very much” improved after using the app for 12 weeks, Ms. Ramiller reported at an oral abstract session at the annual meeting of the American Society of Clinical Oncology (ASCO).

However, the investigators did not report baseline characteristics of patients in each of the study arms, which might have helped to clarify the depth of the effects they saw.

The CBSM program was developed by Michael H. Antoni, PhD, and colleagues in the University of Miami Health System. It is based on cognitive-behavioral therapy but also includes stress management and relaxation techniques to help patients cope with cancer-specific stress.

“”It has been clinically validated and shown to benefit patients with cancer,” Ms. Ramiller said. “However, access is a problem,” she said.

“There aren’t enough qualified, trained providers for the need, and patients with cancer encounter barriers to in-person participation, including things like transportation or financial barriers. So to overcome this, we developed a digitized version of CBSM,” she explained.
 

Impressive and elegant

“Everything about [the study] I thought was very impressive, very elegant, very nicely done,” said invited discussant Raymond U. Osarogiagbon, MBBS, FACP, chief scientist at Baptist Memorial Health Care Corp in Memphis, Tenn.

“They showed efficacy, they showed safety – very nice – user friendliness – very good. Certainly they look like they’re trying to address a highly important, unmet need in a very elegant way. Certainly, they pointed out it needs longer follow-up to see sustainability. We need to see will this work in other settings. Will this be cost-effective? You’ve gotta believe it probably will be,” he said.

CBSM has previously been shown to help patients with cancer reduce stress, improve general and cancer-specific quality of life at various stages of treatment, reduce symptom burden, and improve coping skills, Ms. Ramiller said.

To see whether these benefits could be conveyed digitally rather than in face-to-face encounters, Ms. Ramiller and colleagues worked with Dr. Antoni to develop the CBSM app.

Patients using the app received therapeutic content over 10 sessions with audio, video, and interactive tools that mimicked the sessions they would have received during in-person interventions.

They then compared the app against the control educational app in the randomized, decentralized RESTORE study.
 

High-quality control

Ms. Ramiller said that the control app set “a high bar.”

“The control also offered 10 interactive self-guided sessions. Both treatment apps were professionally designed and visually similar in styling, and they were presented as digital therapeutic-specific for cancer patients. And they were also in a match condition, meaning they received the same attention from study staff and cadence of reminders, but importantly, only the intervention app was based on CBSM,” she explained.

A total of 449 patients with cancers of stage I–III who were undergoing active systemic treatment or were planning to undergo such treatment within 6 months were randomly assigned to the CBSM app or the control app.

The CBSM app was superior to the control app for the primary outcome of anxiety reduction over baseline, as measured at 4, 8 and 12 weeks by the Patient-Reported Outcomes Measurement Information System Anxiety Scale (PROMIS-A) (beta = -.03; P = .019).

CBSM was also significantly better than the control app for the secondary endpoints of reducing symptoms of depression, as measured by the PROMIS-D scale (beta = -.02, P = .042), and also at increasing the percentage of patients who reported improvement in anxiety and depression symptoms on the Patient Global Impression of Change instrument (P < .001)

An extension study of the durability of the effects at 3 and 6 months is underway.

The investigators noted that the incremental cost of management of anxiety or depression is greater than $17,000 per patient per year.

“One of the big promises of a digital therapeutic like this is that it could potentially reduce costs,” Ms. Ramiller told the audience, but she acknowledged, “More work is really needed, however, to directly test the potential savings.”

The RESTORE study is funded by Blue Note Therapeutics. Dr. Osarogiagbon owns stock in Gilead, Lilly, and Pfizer, has received honoraria from Biodesix and Medscape, and has a consulting or advisory role for the American Cancer Society AstraZeneca, Genentech/Roche, LUNGevity, National Cancer Institute, and Triptych Health Partners.
 

A version of this article originally appeared on Medscape.com.

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

A version of this article first appeared on Medscape.com.

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

A version of this article first appeared on Medscape.com.

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

A version of this article first appeared on Medscape.com.

Oncology fellows who completed diversity, equity, and inclusion (DEI) training report that they feel more confident about responding to different types of discrimination, both when directed at them personally and when directed at others.

The finding comes from a survey conducted after the introduction of DEI training within the Yale Medical Oncology-Hematology Fellowship Program. The study was reported by Norin Ansari, MD, MPH, of Yale Cancer Center, New Haven, Conn., at the annual meeting of the American Society of Clinical Oncology (ASCO).

Dr. Ansari emphasized the DEI curriculum in fellowship programs by highlighting the racial and gender disparities that exist among physicians.

“There is a significant representation problem – only 2%-3% of practicing oncologists are Black or Hispanic/Latino,” she said. “And that representation decreases with each stage in the pipeline of the workforce.”

Dr. Ansari also noted gender disparities in the oncologist workforce, reporting that about one-third of faculty positions are held by women.

The anonymous survey was sent to 29 fellows; 23 responded, including 8 first-year fellows and 13 senior fellows. Over 57% of respondents rated the importance of DEI education as 10 on a 10-point scale (mean, 8.6).

At the start of this year, the responses of senior fellows who had already received some DEI training during the previous year’s lecture series were compared with first-year fellows who had not had any fellowship DEI education.

First-year fellows reported a mean confidence score of 2.5/5 at navigating bias and microaggressions when experienced personally and a mean score of 2.9/5 when they were directed at others. Senior fellows reported mean confidence scores of 3 and 3.2, respectively.

Yale then compared longitudinal data on fellows’ comfort levels in navigating discrimination in 2021, 2022, and 2023 a month before the ASCO meeting.

Fellows were asked to rate their comfort level from 1 to 10 in navigating different types of discrimination, including racial inequality, sexual harassment, and gender discrimination. In these three categories, fellows rated comfortability as a 5 in 2021 and as 7 in 2023 after the DEI training.

“Our first goal is to normalize talking about DEI and to recognize that different people in our workforce have different experiences and how we can be allies for them and for our patients,” Dr. Ansari said. “And I think for long-term goals we want to take stock of who’s at the table, who’s making decisions, and how does that affect our field, our science, and our patients.”

Yale designed the 3-year longitudinal curriculum with two annual core topics: upstander training and journal club for discussion and reflection. An additional two to three training sessions per year will focus on either race, gender, LGBTQ+, disability, religion, or implicit bias training.

The most popular topics among fellows were upstander training, cancer treatment and outcomes disparities, recruitment and retention, and career promotion and pay disparities.

The preferred platforms of content delivery were lectures from experts in the field, affinity groups or mentorship links, small group discussions, and advocacy education.

Gerald Hsu, MD, PhD, with the San Francisco VA Medical Center, discussed the results of Yale’s DEI curriculum assessment, saying it represented “best practices” in the industry. However, he acknowledged that realistically, not everyone will be receptive to DEI training.

Dr. Hsu said that holding medical staff accountable is the only way to truly incorporate DEI into everyday practice.

“Collectively, we need to be holding ourselves to different standards or holding ourselves to some standard,” Dr. Hsu said. “Maybe we need to be setting goals to the degree to which we diversify our training programs and our faculty, and there needs to be consequences to not doing so.”

No funding for the study was reported.

A version of this article first appeared on Medscape.com.

Oncology fellows who completed diversity, equity, and inclusion (DEI) training report that they feel more confident about responding to different types of discrimination, both when directed at them personally and when directed at others.

The finding comes from a survey conducted after the introduction of DEI training within the Yale Medical Oncology-Hematology Fellowship Program. The study was reported by Norin Ansari, MD, MPH, of Yale Cancer Center, New Haven, Conn., at the annual meeting of the American Society of Clinical Oncology (ASCO).

Dr. Ansari emphasized the DEI curriculum in fellowship programs by highlighting the racial and gender disparities that exist among physicians.

“There is a significant representation problem – only 2%-3% of practicing oncologists are Black or Hispanic/Latino,” she said. “And that representation decreases with each stage in the pipeline of the workforce.”

Dr. Ansari also noted gender disparities in the oncologist workforce, reporting that about one-third of faculty positions are held by women.

The anonymous survey was sent to 29 fellows; 23 responded, including 8 first-year fellows and 13 senior fellows. Over 57% of respondents rated the importance of DEI education as 10 on a 10-point scale (mean, 8.6).

At the start of this year, the responses of senior fellows who had already received some DEI training during the previous year’s lecture series were compared with first-year fellows who had not had any fellowship DEI education.

First-year fellows reported a mean confidence score of 2.5/5 at navigating bias and microaggressions when experienced personally and a mean score of 2.9/5 when they were directed at others. Senior fellows reported mean confidence scores of 3 and 3.2, respectively.

Yale then compared longitudinal data on fellows’ comfort levels in navigating discrimination in 2021, 2022, and 2023 a month before the ASCO meeting.

Fellows were asked to rate their comfort level from 1 to 10 in navigating different types of discrimination, including racial inequality, sexual harassment, and gender discrimination. In these three categories, fellows rated comfortability as a 5 in 2021 and as 7 in 2023 after the DEI training.

“Our first goal is to normalize talking about DEI and to recognize that different people in our workforce have different experiences and how we can be allies for them and for our patients,” Dr. Ansari said. “And I think for long-term goals we want to take stock of who’s at the table, who’s making decisions, and how does that affect our field, our science, and our patients.”

Yale designed the 3-year longitudinal curriculum with two annual core topics: upstander training and journal club for discussion and reflection. An additional two to three training sessions per year will focus on either race, gender, LGBTQ+, disability, religion, or implicit bias training.

The most popular topics among fellows were upstander training, cancer treatment and outcomes disparities, recruitment and retention, and career promotion and pay disparities.

The preferred platforms of content delivery were lectures from experts in the field, affinity groups or mentorship links, small group discussions, and advocacy education.

Gerald Hsu, MD, PhD, with the San Francisco VA Medical Center, discussed the results of Yale’s DEI curriculum assessment, saying it represented “best practices” in the industry. However, he acknowledged that realistically, not everyone will be receptive to DEI training.

Dr. Hsu said that holding medical staff accountable is the only way to truly incorporate DEI into everyday practice.

“Collectively, we need to be holding ourselves to different standards or holding ourselves to some standard,” Dr. Hsu said. “Maybe we need to be setting goals to the degree to which we diversify our training programs and our faculty, and there needs to be consequences to not doing so.”

No funding for the study was reported.

A version of this article first appeared on Medscape.com.

Oncology fellows who completed diversity, equity, and inclusion (DEI) training report that they feel more confident about responding to different types of discrimination, both when directed at them personally and when directed at others.

The finding comes from a survey conducted after the introduction of DEI training within the Yale Medical Oncology-Hematology Fellowship Program. The study was reported by Norin Ansari, MD, MPH, of Yale Cancer Center, New Haven, Conn., at the annual meeting of the American Society of Clinical Oncology (ASCO).

Dr. Ansari emphasized the DEI curriculum in fellowship programs by highlighting the racial and gender disparities that exist among physicians.

“There is a significant representation problem – only 2%-3% of practicing oncologists are Black or Hispanic/Latino,” she said. “And that representation decreases with each stage in the pipeline of the workforce.”

Dr. Ansari also noted gender disparities in the oncologist workforce, reporting that about one-third of faculty positions are held by women.

The anonymous survey was sent to 29 fellows; 23 responded, including 8 first-year fellows and 13 senior fellows. Over 57% of respondents rated the importance of DEI education as 10 on a 10-point scale (mean, 8.6).

At the start of this year, the responses of senior fellows who had already received some DEI training during the previous year’s lecture series were compared with first-year fellows who had not had any fellowship DEI education.

First-year fellows reported a mean confidence score of 2.5/5 at navigating bias and microaggressions when experienced personally and a mean score of 2.9/5 when they were directed at others. Senior fellows reported mean confidence scores of 3 and 3.2, respectively.

Yale then compared longitudinal data on fellows’ comfort levels in navigating discrimination in 2021, 2022, and 2023 a month before the ASCO meeting.

Fellows were asked to rate their comfort level from 1 to 10 in navigating different types of discrimination, including racial inequality, sexual harassment, and gender discrimination. In these three categories, fellows rated comfortability as a 5 in 2021 and as 7 in 2023 after the DEI training.

“Our first goal is to normalize talking about DEI and to recognize that different people in our workforce have different experiences and how we can be allies for them and for our patients,” Dr. Ansari said. “And I think for long-term goals we want to take stock of who’s at the table, who’s making decisions, and how does that affect our field, our science, and our patients.”

Yale designed the 3-year longitudinal curriculum with two annual core topics: upstander training and journal club for discussion and reflection. An additional two to three training sessions per year will focus on either race, gender, LGBTQ+, disability, religion, or implicit bias training.

The most popular topics among fellows were upstander training, cancer treatment and outcomes disparities, recruitment and retention, and career promotion and pay disparities.

The preferred platforms of content delivery were lectures from experts in the field, affinity groups or mentorship links, small group discussions, and advocacy education.

Gerald Hsu, MD, PhD, with the San Francisco VA Medical Center, discussed the results of Yale’s DEI curriculum assessment, saying it represented “best practices” in the industry. However, he acknowledged that realistically, not everyone will be receptive to DEI training.

Dr. Hsu said that holding medical staff accountable is the only way to truly incorporate DEI into everyday practice.

“Collectively, we need to be holding ourselves to different standards or holding ourselves to some standard,” Dr. Hsu said. “Maybe we need to be setting goals to the degree to which we diversify our training programs and our faculty, and there needs to be consequences to not doing so.”

No funding for the study was reported.

A version of this article first appeared on Medscape.com.

On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.

Seven months later, doctors and their patients are facing the unimaginable: In California, Virginia, and everywhere in between, they are being forced into grim contemplation of untested rationing plans for breast, cervical, bladder, ovarian, lung, testicular, and other cancers. Their decisions are likely to result in preventable deaths.

Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.

The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.

But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?

“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”

“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.

“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”

The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.

Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.

“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”

Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.

At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.

On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.

She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”

Doses remained at 80%, she said. Things hadn’t changed 10 days later.
 

Generics manufacturers are pulling out

The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.

As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.

The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.

Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.

The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.

Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.

Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”

Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.

“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
 

Should government step in?

Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.

As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.

Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”

More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.

“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.

Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.

In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.

“It would almost literally be a drop in the bucket.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.

On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.

Seven months later, doctors and their patients are facing the unimaginable: In California, Virginia, and everywhere in between, they are being forced into grim contemplation of untested rationing plans for breast, cervical, bladder, ovarian, lung, testicular, and other cancers. Their decisions are likely to result in preventable deaths.

Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.

The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.

But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?

“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”

“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.

“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”

The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.

Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.

“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”

Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.

At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.

On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.

She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”

Doses remained at 80%, she said. Things hadn’t changed 10 days later.
 

Generics manufacturers are pulling out

The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.

As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.

The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.

Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.

The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.

Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.

Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”

Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.

“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
 

Should government step in?

Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.

As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.

Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”

More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.

“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.

Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.

In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.

“It would almost literally be a drop in the bucket.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.

On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.

Seven months later, doctors and their patients are facing the unimaginable: In California, Virginia, and everywhere in between, they are being forced into grim contemplation of untested rationing plans for breast, cervical, bladder, ovarian, lung, testicular, and other cancers. Their decisions are likely to result in preventable deaths.

Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.

The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.

But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?

“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”

“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.

“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”

The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.

Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.

“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”

Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.

At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.

On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.

She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”

Doses remained at 80%, she said. Things hadn’t changed 10 days later.
 

Generics manufacturers are pulling out

The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.

As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.

The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.

Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.

The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.

Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.

Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”

Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.

“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
 

Should government step in?

Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.

As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.

Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”

More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.

“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.

Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.

In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.

“It would almost literally be a drop in the bucket.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.