Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

Melanoma is the most lethal skin cancer and is the second most common cancer in adolescents and young adults.¹ It is the fifth most common cancer in the United States based on incidence, which has steadily risen for the last 2 decades.^2,3 For melanoma management, delayed initial diagnosis has been associated with more advanced lesions at presentation and poorer outcomes.⁴ However, the prognostic implications of delaying melanoma management after diagnosis merits further scrutiny.

This study investigates the associations between melanoma treatment delay (MTD) and patient and tumor characteristics. Although most cases undergo surgical treatment first, more advanced stages may require initiating chemotherapy, radiation therapy, or immunotherapy. In addition, patients who are poor surgical candidates may opt for topical field therapy, such as imiquimod for superficial lesions, prior to more definitive treatment.⁵ In the Medicaid population, patients who are older than 85 years, married, and previously diagnosed with another melanoma and who also have an increased comorbidity burden have a higher likelihood of MTD.⁶ For nonmelanoma skin cancers, patient denial is the most common patient-specific factor accounting for treatment delay.⁷ For this study, our aim was to further evaluate the independent risk factors associated with MTD.

Methods

Case Selection
The National Cancer Database (NCDB) was queried for all cutaneous melanoma cases from 2004 to 2015 (N=525,271). The NCDB is an oncology database sourced from more than 1500 accredited cancer facilities in the United States and Puerto Rico. It receives cases from academic hospitals, Veterans Health Administration hospitals, and community centers.⁸ Annually, the database collects approximately 70% of cancer diagnoses and 48% of melanoma diagnoses in the United States.^9,10 Per institutional guidelines, this analysis was determined to be exempt from institutional review board approval due to the deidentified nature of the dataset.

The selection scheme is illustrated in Table 1. International Statistical Classification of Diseases and Related Health Problems histology codes 8720/3 through 8780/3 combined with the site and morphology primary codes C44.0 through C44.9 identified all patients with a diagnosis of cutaneous melanoma. Primary site was established with the histology codes in the following manner: C44.0 through C44.4 for head/neck primary, C44.5 for trunk primary, C44.6 through C44.7 for extremity primary, and C44.8 through C44.9 for not otherwise specified. Because the NCDB does not specify cause of death, any cases in which the melanoma diagnosis was not the patient’s primary (or first) cancer diagnosis were excluded because of potential ambiguity. Cases lacking histologic confirmation of the diagnosis after primary site biopsy or cases diagnosed from autopsy reports also were excluded. Reports missing staging data or undergoing palliative management were removed. In total, 104,118 cases met the inclusion criteria.

Results

The final study population included 104,118 patients, most of whom were male (56.4%), white (96.6%), and aged 50 to 74 years (54.4%). Most patients were privately insured (52.6%), had no CD comorbidities (87.5%), and lived in metropolitan cities (80.4%)(Table 3). A large majority (95,473 [91.7%]) of patients received surgery as the first means of treatment, with a smaller portion (863 [0.8%]) having unspecified systemic therapy first. The remaining cases were first treated with chemotherapy (1738 [1.7%]), immunotherapy (382 [0.4%]), or radiation (490 [0.5%]), and the rest did not specify treatment sequence. The tumors were most commonly located on the extremities (40.7%), were stage I (41.2%), and had a Breslow depth of less than 1 mm (41.6%).

Treatment delay averaged 31.55 days, with a median of 27 days. Overall mean MTD increased significantly from 29.74 days in 2004 to 32.55 days in 2015 (2-tailed t test; P<.001)(Figure). A total of 78,957 cases (75.8%) received treatment within 45 days, whereas 2467 cases (2.5%) were postponed past 90 days. On bivariate analysis, age, sex, race, insurance status, Hispanic ethnicity, median annual income of residential zip code, percentage of the population of the patient’s residential zip code with high school degrees, CD score, and academic treatment facility held significant associations with mMTD and sMTD (P<.05)(Table 3). Analyzing bivariate associations with pertinent tumor characteristics—primary site, stage, and Breslow depth—also held significant associations with mMTD and sMTD (P<.001)(Table 4).

Comment

The path to successful melanoma management involves 2 timeframes. One is time to diagnosis and the other is time to treatment. With 24.2% of patients receiving treatment later than 45 days after diagnosis, MTD is common and, according to our results, has increased on average from 2004 to 2015. This delay may be partially explained by a shortage of dermatologists, leading to longer wait times and follow-up.^13,14 Melanoma treatment delay also varied based on insurance status. Unsurprisingly, those with private insurance showed the lowest rates of MTD. Those with no insurance, Medicare, or Medicaid/other government insurance likely faced greater socioeconomic barriers to health care, such as coverage issues.¹⁵ Transportation, low health literacy, and limited work schedule flexibility have been described as additional hurdles to health care that could contribute to this finding.^16,17 Similarly, nonwhite patients, Hispanic patients, and those from zip codes with low high school graduation rates had more MTD. Although these findings may be explained by socioeconomic barriers and heightened distrust of the health care system, it also is important to consider physician accessibility.^18,19

Considering the 2011 Affordable Care Act along with the 2014 Medicaid expansion, our study holds implications on the impact of these legislations on melanoma treatment. Studies have supported expected rises in Medicaid coverage.^20,21 The overall uninsured rate in the United States declined from 16% in 2010 to 9.1% in 2015.²² In our study, the uninsured population showed the highest average MTD rates, though those with Medicaid also had significant MTD. Another treacherous hurdle for patients is the coordination of care among dermatologists, oncologists, general surgeons, plastic surgeons, and Mohs surgeons as a multidisciplinary team. Lott et al⁶ found that patients who received both biopsy and excision from a dermatologist had the shortest treatment delays, whereas those who had a dermatologist biopsy the site and a different surgeon—including Mohs surgeons—excise it experienced significantly greater MTDs (probablility of MTD >45 days was 31% [95% CI, 24%-37%]. This discordant care and referrals could explain the surprising finding that treatment at an academic facility was independently associated with more MTD, possibly due to the care transitions and referrals that disproportionately affect academic centers and multidisciplinary teams, as mentioned above, regarding the transition of care to other physicians (eg, plastic surgeon). A total of 70.1% of our cases treated at academic facilities reported a prior diagnosis at another facility. These results should not dissuade the pursuit of multidisciplinary treatment teams but should raise caution to untimely referrals.

Age, sex, and race were all associated with more MTD. Patients older than 50 years likely face more complex decisions regarding treatment burden, quality of life, and functional outcomes of more aggressive treatments. High rates of surgical refusal for a number of malignancies have been documented in the elderly population,^23-25 which is of particular concern for the high surgery burden of head and neck melanomas,²⁶ as further supported by the findings of more MTD for head and neck primaries. As with elderly patients, patients with higher comorbidity scores and more advanced tumors face similar family–patient care discussions to guide treatment. Additionally, women were more likely to experience MTD, which may be connected to a greater concern for cosmesis²⁷ and necessitate more complex management options, such as Mohs micrographic surgery (a procedure that has gained some support for melanoma excision with the help of immunostaining).²⁸

There are several limitations to this study. Accurate data rely on precise record keeping, reporting, and coding by the contributing institutions. The NCDB case diagnosis is derived from data entry without a centralized review process by experienced dermatopathologists. We could not assess the effects of tumor diameter, as these data were inadequately recorded within the dataset. The NCDB also does not provide details on specific immunotherapy or chemotherapy agents. The NCDB also is a facility-based data source, potentially biasing the melanoma data toward thicker advanced tumors more readily managed at such institutions. Lastly, it is impossible to distinguish between patient-related (ie, difficult decision-making) and health care–related (ie, health care accessibility) delays. Nonetheless, we maintain that minimizing MTD is important for survival outcomes and for limiting the progression of melanomas, regardless of the underlying rationale. We believe that our study expands on conclusions previously limited to a Medicare population.

Conclusion

According to the NCDB, mean MTD has increased significantly from 2004 to 2015. Our results suggest that MTD is relatively common in the United States, thereby increasing the risk for metastases. Higher MTD rates are independently associated with being older than 50 years, female, nonwhite, not privately insured, Hispanic, and treated at an academic facility; having a positive comorbidity history and stage II to IV tumors; and residing in a zip code with a low high school graduation rate. Stage I tumors, primaries not located on the head or neck, and residing in a zip code with a higher median income are associated with lower MTD rates. Policymakers, patients, and dermatologists should better recognize these risk factors to facilitate patient guidance and health equity.

One of the most important goals in the treatment of patients with CP-CML is to avoid the progression to advanced phases, such as accelerated and blast phase, where the treatments are limited and the outcomes inferior. The long term outcomes of patients with lymphoid blast crisis treated with HyperCVAD plus dasatinib was recently reported by Morita et al. The authors reviewed 85 patients (23 with CML- LBP and 62 with newly diagnosed Ph- positive ALL) who received hyper- CVAD plus dasatinib. In the CML- LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML- LBP. Patients with CML- LBP were less likely to achieve deep molecular remission than patients with Ph- positive ALL. The major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). However, the survival outcomes were similar for CML- LBP and Ph- positive ALL: The 5- year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML- LBP (5- year OS rate, 88% vs 57%; P = .04), while in Ph- positive ALL, the outcome was driven by deeper molecular remission: the 5- year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). Although the outcome of CML- LBP has improved with hyper- CVAD plus dasatinib therapy with survival comparable to that of Ph- positive ALL, data with third generation TKI may even improve these outcomes in the near future.

Allogeneic BMT is the ultimate therapy for resistant or intolerant to TKI patients with CP-CML as well as for advances phases of this disease. Since the introduction of TKI the rates of allo BMT had overall decreased, so Yassine and colleagues performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease) and stratified by age into adult and pediatric groups. Overall for adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84%, 66%, 56%, and 88%, respectively. Pooled NRM and relapse were 20% and 19%, respectively. As a conclusion, these results suggest that allo-HCT still is an effective treatment for TKI-resistant or TKI-intolerant CP-CML and the risk-befit ratio is favorable based on the lack of other alternatives.

One of the most important goals in the treatment of patients with CP-CML is to avoid the progression to advanced phases, such as accelerated and blast phase, where the treatments are limited and the outcomes inferior. The long term outcomes of patients with lymphoid blast crisis treated with HyperCVAD plus dasatinib was recently reported by Morita et al. The authors reviewed 85 patients (23 with CML- LBP and 62 with newly diagnosed Ph- positive ALL) who received hyper- CVAD plus dasatinib. In the CML- LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML- LBP. Patients with CML- LBP were less likely to achieve deep molecular remission than patients with Ph- positive ALL. The major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). However, the survival outcomes were similar for CML- LBP and Ph- positive ALL: The 5- year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML- LBP (5- year OS rate, 88% vs 57%; P = .04), while in Ph- positive ALL, the outcome was driven by deeper molecular remission: the 5- year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). Although the outcome of CML- LBP has improved with hyper- CVAD plus dasatinib therapy with survival comparable to that of Ph- positive ALL, data with third generation TKI may even improve these outcomes in the near future.

Allogeneic BMT is the ultimate therapy for resistant or intolerant to TKI patients with CP-CML as well as for advances phases of this disease. Since the introduction of TKI the rates of allo BMT had overall decreased, so Yassine and colleagues performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease) and stratified by age into adult and pediatric groups. Overall for adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84%, 66%, 56%, and 88%, respectively. Pooled NRM and relapse were 20% and 19%, respectively. As a conclusion, these results suggest that allo-HCT still is an effective treatment for TKI-resistant or TKI-intolerant CP-CML and the risk-befit ratio is favorable based on the lack of other alternatives.

One of the most important goals in the treatment of patients with CP-CML is to avoid the progression to advanced phases, such as accelerated and blast phase, where the treatments are limited and the outcomes inferior. The long term outcomes of patients with lymphoid blast crisis treated with HyperCVAD plus dasatinib was recently reported by Morita et al. The authors reviewed 85 patients (23 with CML- LBP and 62 with newly diagnosed Ph- positive ALL) who received hyper- CVAD plus dasatinib. In the CML- LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML- LBP. Patients with CML- LBP were less likely to achieve deep molecular remission than patients with Ph- positive ALL. The major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). However, the survival outcomes were similar for CML- LBP and Ph- positive ALL: The 5- year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML- LBP (5- year OS rate, 88% vs 57%; P = .04), while in Ph- positive ALL, the outcome was driven by deeper molecular remission: the 5- year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). Although the outcome of CML- LBP has improved with hyper- CVAD plus dasatinib therapy with survival comparable to that of Ph- positive ALL, data with third generation TKI may even improve these outcomes in the near future.

Allogeneic BMT is the ultimate therapy for resistant or intolerant to TKI patients with CP-CML as well as for advances phases of this disease. Since the introduction of TKI the rates of allo BMT had overall decreased, so Yassine and colleagues performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease) and stratified by age into adult and pediatric groups. Overall for adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84%, 66%, 56%, and 88%, respectively. Pooled NRM and relapse were 20% and 19%, respectively. As a conclusion, these results suggest that allo-HCT still is an effective treatment for TKI-resistant or TKI-intolerant CP-CML and the risk-befit ratio is favorable based on the lack of other alternatives.

Key clinical point: Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective treatment strategy for patients with chronic-phase chronic myeloid leukemia (CML-CP) who are resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). However, better patient selection and posttransplant strategies are needed to mitigate the risk of relapse.

Major finding: Pooled rates of overall survival, disease-free survival, complete remission, and molecular response in adult allo-HCT recipients were 84% (95% confidence interval [CI], 59%-99%), 66% (95% CI, 59%-73%), 56% (95% CI, 30%-80%), and 88% (95% CI, 62%-98%), respectively. Pooled rates of nonrelapse mortality and relapse were 20% (95% CI, 15%-26%) and 19% (95% CI, 10%-28%), respectively.

Study details: This was a systematic review and meta-analysis of 9 studies including 439 patients with TKI-resistant or intolerant CML-CP who received allo-HCT.

Disclosures: No funding source was identified. MA Moustafa reported consulting for Acrotech Biopharma and MA Kharfan-Dabaja reported consulting for Pharmacyclics and Daiichi Sankyo. Other authors declared no conflicts of interest.

Source: Yassine F et al. Hematol Oncol Stem Cell Ther. 2021 Mar 11. doi: 10.1016/j.hemonc.2021.02.003.

Key clinical point: Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective treatment strategy for patients with chronic-phase chronic myeloid leukemia (CML-CP) who are resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). However, better patient selection and posttransplant strategies are needed to mitigate the risk of relapse.

Major finding: Pooled rates of overall survival, disease-free survival, complete remission, and molecular response in adult allo-HCT recipients were 84% (95% confidence interval [CI], 59%-99%), 66% (95% CI, 59%-73%), 56% (95% CI, 30%-80%), and 88% (95% CI, 62%-98%), respectively. Pooled rates of nonrelapse mortality and relapse were 20% (95% CI, 15%-26%) and 19% (95% CI, 10%-28%), respectively.

Study details: This was a systematic review and meta-analysis of 9 studies including 439 patients with TKI-resistant or intolerant CML-CP who received allo-HCT.

Disclosures: No funding source was identified. MA Moustafa reported consulting for Acrotech Biopharma and MA Kharfan-Dabaja reported consulting for Pharmacyclics and Daiichi Sankyo. Other authors declared no conflicts of interest.

Source: Yassine F et al. Hematol Oncol Stem Cell Ther. 2021 Mar 11. doi: 10.1016/j.hemonc.2021.02.003.

Key clinical point: Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective treatment strategy for patients with chronic-phase chronic myeloid leukemia (CML-CP) who are resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). However, better patient selection and posttransplant strategies are needed to mitigate the risk of relapse.

Major finding: Pooled rates of overall survival, disease-free survival, complete remission, and molecular response in adult allo-HCT recipients were 84% (95% confidence interval [CI], 59%-99%), 66% (95% CI, 59%-73%), 56% (95% CI, 30%-80%), and 88% (95% CI, 62%-98%), respectively. Pooled rates of nonrelapse mortality and relapse were 20% (95% CI, 15%-26%) and 19% (95% CI, 10%-28%), respectively.

Study details: This was a systematic review and meta-analysis of 9 studies including 439 patients with TKI-resistant or intolerant CML-CP who received allo-HCT.

Disclosures: No funding source was identified. MA Moustafa reported consulting for Acrotech Biopharma and MA Kharfan-Dabaja reported consulting for Pharmacyclics and Daiichi Sankyo. Other authors declared no conflicts of interest.

Source: Yassine F et al. Hematol Oncol Stem Cell Ther. 2021 Mar 11. doi: 10.1016/j.hemonc.2021.02.003.

When classifying gastric varices during endoscopy, experts suggest not only describing their location but also their size and whether any high-risk stigmata, such as discolorations and platelet plugs, are present.

In a clinical practice update from the American Gastroenterological Association, Zachary Henry, MD, of the University of Virginia, Charlottesville, and associates also proposed an alternative nomenclature for locating gastric varices (GV). “In practice, most gastroenterologists use the Sarin classification with the main distinction being cardiofundal versus lesser curvature GV. However, the vascular supply and corresponding therapy for GV and esophageal varices are often different, so a merged classification, such as Sarin’s, can be problematic for therapeutic planning purposes,” they wrote in Clinical Gastroenterology and Hepatology, referring to the classification system published by Shiv K. Sarin, MD, DM, and colleagues. They suggested that a merged classification, such as Sarin’s, can be “problematic for therapeutic and planning purposes” because “the vascular supply and corresponding therapy for GV and [esophageal varices] are often different.” Instead, they advised that an “alternative nomenclature based on location within the stomach is clearer and facilitates correlation with vascular imaging.” Another approach is to add risk factors for bleeding, such as an estimate of variceal size and high-risk stigmata (discolored marks, platelet plugs), to Sarin classification.

Diagnosis and treatment of bleeding GV are complex, and multidisciplinary management by hepatologists, interventional radiologists, and interventional endoscopists is optimal, the experts wrote. Data and clinical guidelines do not support primary prophylaxis to prevent bleeding of GV. The authors offered an algorithm for initial management of suspected portal hypertensive GV bleeding based on both endoscopic and vascular anatomy; it includes assessment of circulatory and respiratory status, vasoactive drug administration, antibiotic prophylaxis, and more.

An early goal is confirming bleeding source and attempting to classify the bleeding site; this can be complicated by presence of intragastric blood that obscures the cardia and fundus and underlying GV. Further steps may include temporizing: “Temporizing measures to halt active bleeding are often not the definitive treatment of choice to prevent rebleeding from GV, whereas definitive measures such as endoscopic cyanoacrylate injection (ECI) or endovascular treatments are often not feasible in the acute, diagnostic setting.”

When definitive endoscopic treatment is preferred, ECI of bleeding GV is the therapy of choice because other approaches may be complicated by location and bleeding risk of GV, although band ligation may be appropriate in lesser curve GV. Specific ECI techniques have not been compared directly in studies, according to the update authors; however, “the specific cyanoacrylate agent should favor the fastest polymerization time to avoid embolization and inducing GV bleeding.” This has meant 4-carbon (butyl) preparations are preferred to 8-carbon (octyl) preparations, they noted.

After treatment, endoscopy is performed every 2-4 weeks so that the ECI can be repeated as needed until obliteration is complete. The experts suggested that, after eradication of GV, an endoscopic reevaluation within 3-6 months should be scheduled, then annually thereafter. Any de novo or recurrent GV during the long-term follow-up may require additional imaging and multidisciplinary exploration to determine potential mechanisms and need for alternative treatments, the authors advised.

According to the practice update, transjugular intrahepatic portosystemic shunt can be used when the GV is receiving significant inflow from the coronary vein or the patient has significant complications from portal hypertension. When TIPS is used, the experts suggest also performing endovascular sclerosis or direct embolization of GV, if possible. For patients with a gastrorenal shunt, balloon-occluded retrograde transvenous obliteration (BRTO) of bleeding GV is considered optimal if local expertise is available and the patient lacks severe complications from portal hypertension. Endoscopy should be performed within 48 hours after BRTO to confirm obliteration of the vascular flow. If residual flow is detected, “cyanoacrylate injection should be performed,” the experts wrote. To confirm that GV are obliterated and check for any vascular complications, they suggest performing CT or MR within 4-6 weeks after BRTO and then as clinically indicated. In addition, surveillance endoscopy is important to identify and treat any esophageal varices that could have been worsened by increased portal pressures.

No funding sources were reported. The experts reported having no conflicts of interest.

When classifying gastric varices during endoscopy, experts suggest not only describing their location but also their size and whether any high-risk stigmata, such as discolorations and platelet plugs, are present.

In a clinical practice update from the American Gastroenterological Association, Zachary Henry, MD, of the University of Virginia, Charlottesville, and associates also proposed an alternative nomenclature for locating gastric varices (GV). “In practice, most gastroenterologists use the Sarin classification with the main distinction being cardiofundal versus lesser curvature GV. However, the vascular supply and corresponding therapy for GV and esophageal varices are often different, so a merged classification, such as Sarin’s, can be problematic for therapeutic planning purposes,” they wrote in Clinical Gastroenterology and Hepatology, referring to the classification system published by Shiv K. Sarin, MD, DM, and colleagues. They suggested that a merged classification, such as Sarin’s, can be “problematic for therapeutic and planning purposes” because “the vascular supply and corresponding therapy for GV and [esophageal varices] are often different.” Instead, they advised that an “alternative nomenclature based on location within the stomach is clearer and facilitates correlation with vascular imaging.” Another approach is to add risk factors for bleeding, such as an estimate of variceal size and high-risk stigmata (discolored marks, platelet plugs), to Sarin classification.

Diagnosis and treatment of bleeding GV are complex, and multidisciplinary management by hepatologists, interventional radiologists, and interventional endoscopists is optimal, the experts wrote. Data and clinical guidelines do not support primary prophylaxis to prevent bleeding of GV. The authors offered an algorithm for initial management of suspected portal hypertensive GV bleeding based on both endoscopic and vascular anatomy; it includes assessment of circulatory and respiratory status, vasoactive drug administration, antibiotic prophylaxis, and more.

An early goal is confirming bleeding source and attempting to classify the bleeding site; this can be complicated by presence of intragastric blood that obscures the cardia and fundus and underlying GV. Further steps may include temporizing: “Temporizing measures to halt active bleeding are often not the definitive treatment of choice to prevent rebleeding from GV, whereas definitive measures such as endoscopic cyanoacrylate injection (ECI) or endovascular treatments are often not feasible in the acute, diagnostic setting.”

When definitive endoscopic treatment is preferred, ECI of bleeding GV is the therapy of choice because other approaches may be complicated by location and bleeding risk of GV, although band ligation may be appropriate in lesser curve GV. Specific ECI techniques have not been compared directly in studies, according to the update authors; however, “the specific cyanoacrylate agent should favor the fastest polymerization time to avoid embolization and inducing GV bleeding.” This has meant 4-carbon (butyl) preparations are preferred to 8-carbon (octyl) preparations, they noted.

After treatment, endoscopy is performed every 2-4 weeks so that the ECI can be repeated as needed until obliteration is complete. The experts suggested that, after eradication of GV, an endoscopic reevaluation within 3-6 months should be scheduled, then annually thereafter. Any de novo or recurrent GV during the long-term follow-up may require additional imaging and multidisciplinary exploration to determine potential mechanisms and need for alternative treatments, the authors advised.

According to the practice update, transjugular intrahepatic portosystemic shunt can be used when the GV is receiving significant inflow from the coronary vein or the patient has significant complications from portal hypertension. When TIPS is used, the experts suggest also performing endovascular sclerosis or direct embolization of GV, if possible. For patients with a gastrorenal shunt, balloon-occluded retrograde transvenous obliteration (BRTO) of bleeding GV is considered optimal if local expertise is available and the patient lacks severe complications from portal hypertension. Endoscopy should be performed within 48 hours after BRTO to confirm obliteration of the vascular flow. If residual flow is detected, “cyanoacrylate injection should be performed,” the experts wrote. To confirm that GV are obliterated and check for any vascular complications, they suggest performing CT or MR within 4-6 weeks after BRTO and then as clinically indicated. In addition, surveillance endoscopy is important to identify and treat any esophageal varices that could have been worsened by increased portal pressures.

No funding sources were reported. The experts reported having no conflicts of interest.

When classifying gastric varices during endoscopy, experts suggest not only describing their location but also their size and whether any high-risk stigmata, such as discolorations and platelet plugs, are present.

In a clinical practice update from the American Gastroenterological Association, Zachary Henry, MD, of the University of Virginia, Charlottesville, and associates also proposed an alternative nomenclature for locating gastric varices (GV). “In practice, most gastroenterologists use the Sarin classification with the main distinction being cardiofundal versus lesser curvature GV. However, the vascular supply and corresponding therapy for GV and esophageal varices are often different, so a merged classification, such as Sarin’s, can be problematic for therapeutic planning purposes,” they wrote in Clinical Gastroenterology and Hepatology, referring to the classification system published by Shiv K. Sarin, MD, DM, and colleagues. They suggested that a merged classification, such as Sarin’s, can be “problematic for therapeutic and planning purposes” because “the vascular supply and corresponding therapy for GV and [esophageal varices] are often different.” Instead, they advised that an “alternative nomenclature based on location within the stomach is clearer and facilitates correlation with vascular imaging.” Another approach is to add risk factors for bleeding, such as an estimate of variceal size and high-risk stigmata (discolored marks, platelet plugs), to Sarin classification.

Diagnosis and treatment of bleeding GV are complex, and multidisciplinary management by hepatologists, interventional radiologists, and interventional endoscopists is optimal, the experts wrote. Data and clinical guidelines do not support primary prophylaxis to prevent bleeding of GV. The authors offered an algorithm for initial management of suspected portal hypertensive GV bleeding based on both endoscopic and vascular anatomy; it includes assessment of circulatory and respiratory status, vasoactive drug administration, antibiotic prophylaxis, and more.

An early goal is confirming bleeding source and attempting to classify the bleeding site; this can be complicated by presence of intragastric blood that obscures the cardia and fundus and underlying GV. Further steps may include temporizing: “Temporizing measures to halt active bleeding are often not the definitive treatment of choice to prevent rebleeding from GV, whereas definitive measures such as endoscopic cyanoacrylate injection (ECI) or endovascular treatments are often not feasible in the acute, diagnostic setting.”

When definitive endoscopic treatment is preferred, ECI of bleeding GV is the therapy of choice because other approaches may be complicated by location and bleeding risk of GV, although band ligation may be appropriate in lesser curve GV. Specific ECI techniques have not been compared directly in studies, according to the update authors; however, “the specific cyanoacrylate agent should favor the fastest polymerization time to avoid embolization and inducing GV bleeding.” This has meant 4-carbon (butyl) preparations are preferred to 8-carbon (octyl) preparations, they noted.

After treatment, endoscopy is performed every 2-4 weeks so that the ECI can be repeated as needed until obliteration is complete. The experts suggested that, after eradication of GV, an endoscopic reevaluation within 3-6 months should be scheduled, then annually thereafter. Any de novo or recurrent GV during the long-term follow-up may require additional imaging and multidisciplinary exploration to determine potential mechanisms and need for alternative treatments, the authors advised.

According to the practice update, transjugular intrahepatic portosystemic shunt can be used when the GV is receiving significant inflow from the coronary vein or the patient has significant complications from portal hypertension. When TIPS is used, the experts suggest also performing endovascular sclerosis or direct embolization of GV, if possible. For patients with a gastrorenal shunt, balloon-occluded retrograde transvenous obliteration (BRTO) of bleeding GV is considered optimal if local expertise is available and the patient lacks severe complications from portal hypertension. Endoscopy should be performed within 48 hours after BRTO to confirm obliteration of the vascular flow. If residual flow is detected, “cyanoacrylate injection should be performed,” the experts wrote. To confirm that GV are obliterated and check for any vascular complications, they suggest performing CT or MR within 4-6 weeks after BRTO and then as clinically indicated. In addition, surveillance endoscopy is important to identify and treat any esophageal varices that could have been worsened by increased portal pressures.

No funding sources were reported. The experts reported having no conflicts of interest.

Key clinical point: Hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) plus dasatinib therapy has improved clinical outcomes in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP) with survival comparable to that of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL).

Major finding: Five-year overall (59% vs. 48%; P = .97) and progression-free (46% vs. 44%; P = .88) survival rates were similar in patients with CML-LBP and Ph-positive ALL.

Study details: This retrospective study included 23 and 62 patients with CML-LBP and newly diagnosed Ph-positive ALL, respectively, who were treated with hyper-CVAD plus dasatinib.

Disclosures: This work was supported in part by Cancer Center Support Grant to the University of Texas, MD Anderson. Some investigators reported honoraria, research grants, consulting fees, personal fees, patent and royalties, and membership on the board of directors or advisory committees from various pharmaceutical companies.

Source: Morita K et al. Cancer. 2021 Apr 6. doi: 10.1002/cncr.33539.

Key clinical point: Hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) plus dasatinib therapy has improved clinical outcomes in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP) with survival comparable to that of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL).

Major finding: Five-year overall (59% vs. 48%; P = .97) and progression-free (46% vs. 44%; P = .88) survival rates were similar in patients with CML-LBP and Ph-positive ALL.

Study details: This retrospective study included 23 and 62 patients with CML-LBP and newly diagnosed Ph-positive ALL, respectively, who were treated with hyper-CVAD plus dasatinib.

Disclosures: This work was supported in part by Cancer Center Support Grant to the University of Texas, MD Anderson. Some investigators reported honoraria, research grants, consulting fees, personal fees, patent and royalties, and membership on the board of directors or advisory committees from various pharmaceutical companies.

Source: Morita K et al. Cancer. 2021 Apr 6. doi: 10.1002/cncr.33539.

Key clinical point: Hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) plus dasatinib therapy has improved clinical outcomes in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP) with survival comparable to that of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL).

Major finding: Five-year overall (59% vs. 48%; P = .97) and progression-free (46% vs. 44%; P = .88) survival rates were similar in patients with CML-LBP and Ph-positive ALL.

Study details: This retrospective study included 23 and 62 patients with CML-LBP and newly diagnosed Ph-positive ALL, respectively, who were treated with hyper-CVAD plus dasatinib.

Disclosures: This work was supported in part by Cancer Center Support Grant to the University of Texas, MD Anderson. Some investigators reported honoraria, research grants, consulting fees, personal fees, patent and royalties, and membership on the board of directors or advisory committees from various pharmaceutical companies.

Source: Morita K et al. Cancer. 2021 Apr 6. doi: 10.1002/cncr.33539.

Key clinical point: Nilotinib treatment for chronic myeloid leukemia (CML) may be associated with arterial complications, particularly involving the carotid artery. These results urge for cardiovascular evaluation, with close vascular follow-up, in all patients initiating nilotinib.

Major finding: Arterial ultrasound anomalies were present in 25 patients, with the carotid bulb being the most involved territory (44%). Overall, vascular arterial anomaly was present in 33.8% of patients. Vascular adverse events were also present in 12.5% of patients with no cardiovascular risk factors.

Study details: This retrospective study evaluated 74 patients with CML treated with nilotinib at the Paoli-Calmettes Institute, Marseille, between 2006 and 2015.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Sarlon-Bartoli G et al. J Med Vasc. 2021 Mar 6. doi: 10.1016/j.jdmv.2021.02.002.

Key clinical point: Nilotinib treatment for chronic myeloid leukemia (CML) may be associated with arterial complications, particularly involving the carotid artery. These results urge for cardiovascular evaluation, with close vascular follow-up, in all patients initiating nilotinib.

Major finding: Arterial ultrasound anomalies were present in 25 patients, with the carotid bulb being the most involved territory (44%). Overall, vascular arterial anomaly was present in 33.8% of patients. Vascular adverse events were also present in 12.5% of patients with no cardiovascular risk factors.

Study details: This retrospective study evaluated 74 patients with CML treated with nilotinib at the Paoli-Calmettes Institute, Marseille, between 2006 and 2015.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Sarlon-Bartoli G et al. J Med Vasc. 2021 Mar 6. doi: 10.1016/j.jdmv.2021.02.002.

Key clinical point: Nilotinib treatment for chronic myeloid leukemia (CML) may be associated with arterial complications, particularly involving the carotid artery. These results urge for cardiovascular evaluation, with close vascular follow-up, in all patients initiating nilotinib.

Major finding: Arterial ultrasound anomalies were present in 25 patients, with the carotid bulb being the most involved territory (44%). Overall, vascular arterial anomaly was present in 33.8% of patients. Vascular adverse events were also present in 12.5% of patients with no cardiovascular risk factors.

Study details: This retrospective study evaluated 74 patients with CML treated with nilotinib at the Paoli-Calmettes Institute, Marseille, between 2006 and 2015.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Sarlon-Bartoli G et al. J Med Vasc. 2021 Mar 6. doi: 10.1016/j.jdmv.2021.02.002.

Key clinical point: With broader use of novel tyrosine kinase inhibitor (TKI) and a better understanding of the disease, the relative survival (RS) of patients with chronic myeloid leukemia (CML) in the United States has improved but is still not on par with the general population.

Major finding: Overall, rates of 5- and 10-year RS were 83.4% (95% confidence interval [CI], 81.6%-85.0%) and 72.8% (95% CI, 69.7%-75.6%), respectively. Ten-year RS was worse among patients aged 65 years or older vs. those aged less than 65 years. The 5-year RS for patients diagnosed between 2008-2014 and 2001-2007 was 87.0% and 81.0%, respectively (P less than .001).

Study details: Findings are from a US population-based study, including 3,946 patients diagnosed with BCR-ABL–positive CML during the period between the introduction of TKIs and the last available follow-up data (2001-2014).

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Jamy O et al. Am J Hematol. 2021 Apr 17. doi: 10.1002/ajh.26195.

Key clinical point: With broader use of novel tyrosine kinase inhibitor (TKI) and a better understanding of the disease, the relative survival (RS) of patients with chronic myeloid leukemia (CML) in the United States has improved but is still not on par with the general population.

Major finding: Overall, rates of 5- and 10-year RS were 83.4% (95% confidence interval [CI], 81.6%-85.0%) and 72.8% (95% CI, 69.7%-75.6%), respectively. Ten-year RS was worse among patients aged 65 years or older vs. those aged less than 65 years. The 5-year RS for patients diagnosed between 2008-2014 and 2001-2007 was 87.0% and 81.0%, respectively (P less than .001).

Study details: Findings are from a US population-based study, including 3,946 patients diagnosed with BCR-ABL–positive CML during the period between the introduction of TKIs and the last available follow-up data (2001-2014).

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Jamy O et al. Am J Hematol. 2021 Apr 17. doi: 10.1002/ajh.26195.

Key clinical point: With broader use of novel tyrosine kinase inhibitor (TKI) and a better understanding of the disease, the relative survival (RS) of patients with chronic myeloid leukemia (CML) in the United States has improved but is still not on par with the general population.

Major finding: Overall, rates of 5- and 10-year RS were 83.4% (95% confidence interval [CI], 81.6%-85.0%) and 72.8% (95% CI, 69.7%-75.6%), respectively. Ten-year RS was worse among patients aged 65 years or older vs. those aged less than 65 years. The 5-year RS for patients diagnosed between 2008-2014 and 2001-2007 was 87.0% and 81.0%, respectively (P less than .001).

Study details: Findings are from a US population-based study, including 3,946 patients diagnosed with BCR-ABL–positive CML during the period between the introduction of TKIs and the last available follow-up data (2001-2014).

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Source: Jamy O et al. Am J Hematol. 2021 Apr 17. doi: 10.1002/ajh.26195.

Key clinical point: Gastrointestinal adverse event (AE) profiles differed significantly among different tyrosine kinase inhibitors (TKIs) and should be considered for optimal therapy selection for patients with chronic-phase chronic myeloid leukemia (CML-CP).

Major finding: The mean incidence of all gastrointestinal AEs was highest with bosutinib (52.9%), followed by imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). The incidence of most gastrointestinal AEs was consistently and significantly higher for bosutinib and lower for nilotinib vs. other TKIs (P less than .0016). Overall survival rates over 12 months were more than 90% for all TKIs.

Study details: Meta-analysis of 43 peer-reviewed studies including a heterogeneous population of 10,789 patients with CML with varying disease stages.

Disclosures: This study was funded by Georgia Institute of Technology President’s Undergraduate Research Award, a grant from Incyte pharmaceuticals, Children’s Hospital of Atlanta Aflac pilot grant, and National Science Foundation CAREER award. V Kota reported honoraria for consultancy from Novartis and Pfizer. Other authors declared no conflicts of interest.

Source: Mohanavelu P et al. Cancers. 2021 Apr 1. doi: 10.3390/cancers13071643.

Key clinical point: Gastrointestinal adverse event (AE) profiles differed significantly among different tyrosine kinase inhibitors (TKIs) and should be considered for optimal therapy selection for patients with chronic-phase chronic myeloid leukemia (CML-CP).

Major finding: The mean incidence of all gastrointestinal AEs was highest with bosutinib (52.9%), followed by imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). The incidence of most gastrointestinal AEs was consistently and significantly higher for bosutinib and lower for nilotinib vs. other TKIs (P less than .0016). Overall survival rates over 12 months were more than 90% for all TKIs.

Study details: Meta-analysis of 43 peer-reviewed studies including a heterogeneous population of 10,789 patients with CML with varying disease stages.

Disclosures: This study was funded by Georgia Institute of Technology President’s Undergraduate Research Award, a grant from Incyte pharmaceuticals, Children’s Hospital of Atlanta Aflac pilot grant, and National Science Foundation CAREER award. V Kota reported honoraria for consultancy from Novartis and Pfizer. Other authors declared no conflicts of interest.

Source: Mohanavelu P et al. Cancers. 2021 Apr 1. doi: 10.3390/cancers13071643.

Key clinical point: Gastrointestinal adverse event (AE) profiles differed significantly among different tyrosine kinase inhibitors (TKIs) and should be considered for optimal therapy selection for patients with chronic-phase chronic myeloid leukemia (CML-CP).

Major finding: The mean incidence of all gastrointestinal AEs was highest with bosutinib (52.9%), followed by imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). The incidence of most gastrointestinal AEs was consistently and significantly higher for bosutinib and lower for nilotinib vs. other TKIs (P less than .0016). Overall survival rates over 12 months were more than 90% for all TKIs.

Study details: Meta-analysis of 43 peer-reviewed studies including a heterogeneous population of 10,789 patients with CML with varying disease stages.

Disclosures: This study was funded by Georgia Institute of Technology President’s Undergraduate Research Award, a grant from Incyte pharmaceuticals, Children’s Hospital of Atlanta Aflac pilot grant, and National Science Foundation CAREER award. V Kota reported honoraria for consultancy from Novartis and Pfizer. Other authors declared no conflicts of interest.

Source: Mohanavelu P et al. Cancers. 2021 Apr 1. doi: 10.3390/cancers13071643.

Key clinical point: Bosutinib demonstrated comparable efficacy to nilotinib and dasatinib for first-line treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP).

Major finding: Besides bosutinib demonstrating better deep molecular responses, MR4 vs. nilotinib (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.38-0.84) and MR4.5 vs. dasatinib (OR, 0.56; 95% CI, 0.35-0.90) at 24 months, other parameters like major molecular response, complete cytogenetic response, and disease progression by 24 months were similar with bosutinib vs. nilotinib and dasatinib.

Study details: Unanchored matching-adjusted indirect treatment comparisons were performed using data from bosutinib (BFORE), nilotinib (ENESTnd), and dasatinib (DASISION) trials.

Disclosures: This study was sponsored by Pfizer. The authors including the lead author reported being an employee and/or share or equity holders of Ingress-health BV, which received financial assistance from Pfizer for the conduct of the study.

Source: Muresan B et al. Curr Med Res Opin. 2021 Apr 2. doi: 10.1080/03007995.2021.1896489.

Key clinical point: Bosutinib demonstrated comparable efficacy to nilotinib and dasatinib for first-line treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP).

Major finding: Besides bosutinib demonstrating better deep molecular responses, MR4 vs. nilotinib (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.38-0.84) and MR4.5 vs. dasatinib (OR, 0.56; 95% CI, 0.35-0.90) at 24 months, other parameters like major molecular response, complete cytogenetic response, and disease progression by 24 months were similar with bosutinib vs. nilotinib and dasatinib.

Study details: Unanchored matching-adjusted indirect treatment comparisons were performed using data from bosutinib (BFORE), nilotinib (ENESTnd), and dasatinib (DASISION) trials.

Disclosures: This study was sponsored by Pfizer. The authors including the lead author reported being an employee and/or share or equity holders of Ingress-health BV, which received financial assistance from Pfizer for the conduct of the study.

Source: Muresan B et al. Curr Med Res Opin. 2021 Apr 2. doi: 10.1080/03007995.2021.1896489.

Key clinical point: Bosutinib demonstrated comparable efficacy to nilotinib and dasatinib for first-line treatment of newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP).

Major finding: Besides bosutinib demonstrating better deep molecular responses, MR4 vs. nilotinib (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.38-0.84) and MR4.5 vs. dasatinib (OR, 0.56; 95% CI, 0.35-0.90) at 24 months, other parameters like major molecular response, complete cytogenetic response, and disease progression by 24 months were similar with bosutinib vs. nilotinib and dasatinib.

Study details: Unanchored matching-adjusted indirect treatment comparisons were performed using data from bosutinib (BFORE), nilotinib (ENESTnd), and dasatinib (DASISION) trials.

Disclosures: This study was sponsored by Pfizer. The authors including the lead author reported being an employee and/or share or equity holders of Ingress-health BV, which received financial assistance from Pfizer for the conduct of the study.

Source: Muresan B et al. Curr Med Res Opin. 2021 Apr 2. doi: 10.1080/03007995.2021.1896489.