Federal Practitioner

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

In patients with T-cell lymphoma, allogeneic transplant can lead to durable remissions among patients who might otherwise have poor outcomes, results of a large retrospective observational study suggest.

Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.

“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.

Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.

Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.

Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.

Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.

“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.

“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.

The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.

At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.

Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.

Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.

There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.

Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.

Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.

While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.

“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.

“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”

Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.

Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
 

SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.

In patients with T-cell lymphoma, allogeneic transplant can lead to durable remissions among patients who might otherwise have poor outcomes, results of a large retrospective observational study suggest.

Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.

“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.

Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.

Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.

Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.

Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.

“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.

“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.

The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.

At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.

Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.

Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.

There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.

Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.

Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.

While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.

“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.

“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”

Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.

Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
 

SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.

In patients with T-cell lymphoma, allogeneic transplant can lead to durable remissions among patients who might otherwise have poor outcomes, results of a large retrospective observational study suggest.

Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.

“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.

Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.

Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.

Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.

Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.

“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.

“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.

The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.

At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.

Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.

Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.

There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.

Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.

Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.

While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.

“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.

“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”

Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.

Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
 

SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

Patients with hematologic disease who develop COVID-19 may experience substantial morbidity and mortality related to SARS-CoV-2 infection, according to recent registry data reported at the all-virtual annual meeting of the American Society of Hematology.

Overall mortality was 28% for the first 250 patients entered into the ASH Research Collaborative COVID-19 Registry for Hematology, researchers reported in an abstract of their study findings.

However, the burden of death and moderate-to-severe COVID-19 outcomes was highest in patients with poorer prognosis and those with relapsed/refractory hematological disease, they added.

The most commonly represented malignancies were acute leukemia, non-Hodgkin lymphoma, and myeloma or amyloidosis, according to the report.

Taken together, the findings do support an “emerging consensus” that COVID-19 related morbidity and mortality is significant in these patients, authors said – however, the current findings may not be reason enough to support a change in treatment course for the underlying disease.

“We see no reason, based on our data, to withhold intensive therapies from patients with underlying hematologic malignancies and favorable prognoses, if aggressive supportive care is consistent with patient preferences,” wrote the researchers.

ASH President Stephanie Lee, MD, MPH, said these registry findings are important to better understand how SARS-CoV-2 is affecting not only patients with hematologic diseases, but also individuals who experience COVID-19-related hematologic complications.

However, the findings are limited due to the heterogeneity of diseases, symptoms, and treatments represented in the registry, said Dr. Lee, associate director of the clinical research division at Fred Hutchinson Cancer Center in Seattle.

“More data will be coming in, but I think this is an example of trying to harness real-world information to try to learn things until we get more controlled studies,” Dr. Lee said in a media briefing held in advance of the ASH meeting.
 

Comorbidities and more

Patients with blood cancers are often older and may have comorbidities such as diabetes or hypertension that have been linked to poor COVID-19 outcomes, according to the authors of the report, led by William A. Wood, MD, MPH, associate professor of medicine with the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Moreover, these patients may have underlying immune dysfunction and may receive chemotherapy or immunotherapy that is “profoundly immunosuppressive,” Dr. Wood and coauthors said in their report.

To date, however, risks of morbidity and mortality related to SARS-CoV-2 infection have not been well defined in this patient population, authors said.

More data is emerging now from the ASH Research Collaborative COVID-19 Registry for Hematology, which includes data on patients positive for COVID-19 who have a past or present hematologic condition or have experienced a hematologic complication related to COVID-19.

All data from the registry is being made available through a dashboard on the ASH Research Collaborative website, which as of Dec. 1, 2020, included 693 complete cases.

The data cut in the ASH abstract includes the first 250 patients enrolled at 74 sites around the world, the authors said. The most common malignancies included acute leukemia in 33%, non-Hodgkin lymphoma in 27%, and myeloma or amyloidosis in 16%.

The most frequently reported symptoms included fever in 73%, cough in 67%, dyspnea in 50%, and fatigue in 40%, according to that report.

At the time of this data snapshot, treatment with COVID-19-directed therapies including hydroxychloroquine or azithromycin were common, reported in 76 and 59 patients, respectively, in the cohort.

Batch submissions from sites with high incidence of COVID-19 infection are ongoing. The registry has been expanded to include nonmalignant hematologic diseases, and the registry will continue to accumulate data as a resource for the hematology community.

Overall mortality was 28% at the time, according to the abstract, with nearly all of the deaths occurring in patients classified as having COVID-19 that was moderate (i.e., requiring hospitalization) or severe (i.e., requiring ICU admission).

“In some instances, death occurred after a decision was made to forgo ICU admission in favor of a palliative approach,” said Dr. Wood and coauthors in their report.

Dr. Wood reported research funding from Pfizer, consultancy with Teladoc/Best Doctors, and honoraria from the ASH Research Collaborative. Coauthors provided disclosures related to Celgene, Madrigal Pharmaceuticals, Pharmacyclics, and Amgen, among others.

SOURCE: Wood WA et al. ASH 2020, Abstract 215.

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

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

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

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

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

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

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.

While cardiovascular mortality rates have declined, heart disease continues to be the leading cause of death in the US, and the number of people with cardiovascular disease (CVD) is rising.¹ CVD is more prevalent among military veterans than it is among nonveterans aged ≥ 25 years, and veteran status is associated with higher risk of incident heart disease after controlling for socioeconomic status, other medical diseases, depression, and lifestyle.^2-4 Combat exposure, posttraumatic stress disorder (PTSD), and Purple Heart commendation are associated with higher rates of CVD, including adverse cardiovascular events.^5-7 Many patients seeking care in the Veterans Health Administration (VHA), including those who undergo cardiac catheterization, meet the criteria for multimorbidity (defined as having ≥ 2 chronic diseases⁸), which is common among veterans.^9,10 Multimorbidity presents a challenge for lifestyle intervention, as different diets may be prescribed to treat different conditions, such as Dietary Approaches to Stop Hypertension, and low-glycemic diet for diabetes mellitus (DM). Veterans with CVD are often clinically complex and may require more multifaceted secondary prevention programs.

During the coronavirus 2019 (COVID-19) pandemic, effective secondary prevention intervention is needed more than ever. Older age, CVD, and common comorbidities, including hypertension, DM, and obesity, place patients at the highest risk for severe COVID-19 infection.¹¹ COVID-19 social distancing encourages vulnerable populations to stay home, which can make engaging in any levels of physical activity more challenging. The International Food Council found that 85% of adults have made a change to their food consumption pattern, including eating more, during the COVID-19 pandemic.¹² Thus, secondary CVD prevention programs for veterans need to provide treatment that addresses these specific challenges and can be delivered via telehealth for continuity of care after disruption of traditional services.

Nutrition may be the most powerful Ornish ICR component. The initial RCT conducted by Ornish and colleagues included only stress management training and a whole-food, plant-based (WFPB) diet, including grains, legumes, vegetables, fruits, nuts, and seeds. The trial found 91% of participants experienced reduced angina after only 24 days.¹⁵ The only single-component intervention study resulting in partial reversal of atherosclerosis was a WFPB diet-only study, which documented regression of atherosclerotic plaques after 5 years, using coronary angiography in 73% of participants, with arrested progression in the other 27%.²² Participants reported no cardiovascular AEs after 12 years.²³ Furthermore, a number of other recent studies have demonstrated the benefits of WFPB diet-only interventions for type 2 DM (T2DM), hypertension, and obesity.^24-27 The Heart Disease Reversal Program (HDRP) was developed to create an interdisciplinary lifestyle intervention that emphasized nutrition for a broad population of veterans with atherosclerotic CVD, of varying levels of functional ability, to promote comprehensive CVD risk reduction and bring heart disease reversal intervention into routine clinical practice.

Program Description 

The Mental Health, Cardiology, and Nutrition and Food services all approved the launch of HDRP. We contacted veterans by mail, and 11% expressed interest (Figure). Among patients who received the initial mailed letter (prior to our accepting staff referrals), only 5% of patients who enrolled in HDRP reported previously being told about or prescribed a WFPB diet by any health care provider (HCP). Currently, patients are primarily referred to HDRP by Cardiology, Primary Care, and Mental Health services.

Design

HDRP is an adaptation of interdisciplinary lifestyle interventions that have resulted in regression of atherosclerotic blockages confirmed with invasive coronary angiography.^15-17,22,28 HDRP currently is offered in a Behavioral Medicine Clinic at the Sacramento US Department of Veterans Affairs (VA) Medical Center (VAMC) in California. Program staff include a clinical health psychologist who organizes, coordinates, and act as the lead facilitator of the program; registered dietitians; clinical pharmacists; and a consulting physician. Patients engage in the 4-month core HDRP program in small cohorts (ie, 6-10 patients), and spouses/partners are highly encouraged to attend all sessions.

Components

Telephone screening. Patients are screened for the inclusion and exclusion criteria (Table 1). Patients engaging in a traditional CR program are included in the screening. Patients are informed that the program consists of lifestyle intervention, including emphasis on following a WFPB diet.

A psychologist delivers the physical activity component. Patients are encouraged to meet the American Heart Association/American College of Cardiology recommendations for aerobic exercise (at least 150 minutes of moderate intensity physical activity per week) through a walking program.³⁵ Patients with medical contraindications (eg, severe pain, mobility restrictions) are encouraged to follow the exercise/activity recommendations they had been given by their primary care provider (PCP), physical therapist, or other HCP.

A psychologist provides evidence-based cognitive behavioral stress management (CBSM) training, adapted from models developed for patients with stable ischemic heart disease, HIV/AIDS, and cancer.^36-38 CBSM is a psychotherapy grounded in stress/coping theory and cognitive behavioral theory of psychopathology that integrates cognitive restructuring, coping skills training, communication/assertiveness training, anger management, and mindfulness/acceptance-based approaches. Additional emphasis is placed on assisting patients’ adjustment to the lifestyle challenges for following a plant-based diet, dealing with food cravings and emotional eating, and connecting lifestyle change to patients’ deepest values and goals.

A clinical pharmacist conducts a medication reconciliation for each patient at baseline. The pharmacist consults with each patient’s PCP, cardiologist, and HDRP consulting physician, as needed, to ensure safe adjustments to medications. Pharmacists also provide education on medications at group sessions.

After completion of the 12-week core program, graduates are encouraged to attend the monthly graduates’ group indefinitely, and as often as they desire to promote maintenance of the disease reversal lifestyle. Patients are encouraged to complete our recommended fasting laboratory work every 3 to 6 months to facilitate maintenance of treatment gains.

Program Evaluation

Patients frequently reported that the group format was vital to their success. Patients requested a cooking class, yet we lacked a full teaching kitchen. Integrating plant-based meal samples at every session and cooking videos helped. Patients reported that 100% adherence to the WFPB diet led to significant changes in their food preferences, including a loss of interest in meat.³⁹ Patients encouraged us to keep the “disease reversal” language and focus. One veteran stated: “Disease reversal, that is the reason I called you when I got your letter.” Showing before and after images of coronary angiograms and cardiac positron emission tomography scans depicting regression of atherosclerotic plaque and restored myocardial perfusion were described as highly motivating and generated willingness to commit to a more aggressive lifestyle change.³¹

Patients routinely stated that they lacked understanding of their laboratory test results, which HDRP remedied. Some patients reported their adult children followed a plant-based diet, and our program resulted in a new commonality and source of bonding that was highly valued. Some patients reported that HDRP was helpful for controlling their COVID-19 anxiety and feeling in control of their health. Satisfaction surveys were completed by participants at the end of the core program, which demonstrated very high satisfaction with and acceptability of HDRP (Table 3).

COVID-19 Response

Face-to-face group appointments were converted to videoconferencing as a result of the COVID-19 pandemic. While HDRP always promoted the use of technology and mHealth tools, the pandemic led us to develop novel technology-based interventions.⁴⁰ One cohort transitioned from in-person to videoconferencing sessions, and 2 cohorts recently started this format and are ongoing. We have successfully used videoconferencing with Cisco Webex, the VA-approved backup platform, as we encountered technical barriers when using VA Video Connect. Program materials were shared electronically, and participants sent blood pressure/sugar logs by secure messaging. Guidance for online grocery shopping with home delivery was provided, and research on the benefits of the HDRP lifestyle on immune function was incorporated.

The stress management component incorporated coping with COVID-19, including normalizing common emotional difficulties with sheltering-in-place and quarantine, acknowledging and processing fear and anxiety related to being at very high risk for severe COVID-19. We presented heart disease reversal as an urgent and feasible goal during the pandemic both reducing risk of premature death and major adverse cardiovascular events in the long-term and also reducing personal risk of severe COVID complications. The new VA COVID Coach app was also presented as a resource. Reputable sources of COVID-19 and public health information were shared. Walking continued to be the primary recommended form of exercise, while indoor home exercise options were promoted during the periods of very poor air quality due to the widespread California fires and smoke.

Considering the research suggesting benefits of our intervention for treating T2DM,promoting sustained weight loss, and promoting comprehensive cardiometabolic risk reduction, we have begun accepting referrals for patients with any type of atherosclerotic CVD (eg, peripheral artery disease, carotid artery disease), patients with T2DM (without CVD), and patients with only a history of ischemic stroke or transient ischemic attack.^24-27 Vascular surgery has become a new referral source, primarily for patients with peripheral and carotid artery diseases. Finally, we are leveraging videoconferencing and accepting referrals across the VA Northern California Health Care System (VANCHCS)catchment (from the California-Oregon state border to the San Francisco Bay Area). This also helps address a long-standing problem with reaching the many rural veterans who live far from a VA clinic. We successfully implemented a consult/referral process within the EHR that is available to providers across VANCHCS.

Discussion

The efficacy and effectiveness of reversal programs are well established in intensive programs (eg, ICR), yet such programs have yet to be streamlined and disseminated broadly into routine clinical care. HDRP has endeavored to address this by emphasizing nutrition relative to other program components. We have learned that the words “disease reversal” are very often the reason patients initially reach out or accept referral to our program.

Consistent with past research on plant-based nutrition interventions, the group format was indispensable.⁴¹ Individual sessions with a clinical health psychologist enabled tailored feedback and education on how behavior changes could impact laboratory results and how certain psychosocial factors could support success. Participants reported that seeing significantly favorable laboratory results was highly motivating and confirmed the power of their lifestyle changes. Furthermore, a psychosocial health assessment with individual sessions promoted a tailored treatment plan with targeted clinical interventions, such as behavioral health education, motivational interviewing, and advanced methods, including cognitive behavioral therapy and techniques drawn from dialectical behavior therapy and acceptance and commitment therapy.

Veterans with multimorbidity face the difficult task of learning and maintaining a complex disease self-management program and implementing a lifestyle approach that is feasible, effective, promotes weight loss, and treats multiple conditions. HDRP is a model approach for this population, as demonstrated by a recent case report of a 65-year-old male veteran with atherosclerotic CVD, T2DM, hypertension, and myasthenia gravis who had 2 heart attacks within 2 months.⁴² His neurologic disease precluded significant physical activity. Although he achieved some initial weight loss through lifestyle changes, he continued to have daily angina despite optimal and aggressive cardiology management. After enrolling in HDRP and adopting the WFPB diet, the patient reported almost complete resolution of angina within 1 month, similar to that found in other studies.¹⁵

The literature suggests that concern over the acceptability of plant-based diets and patients’ ability to adhere to them long-term may be misplaced. A review paper on dietary interventions lasting > 1 year found that 51 to 61% of vegetarian and vegan study participants had maintained dietary adherence, while 20 to 55% of omnivorous diet intervention participants adhered to their study diets.⁴³ Remarkably, there were no statistically significant differences in the acceptability of the vegan, vegetarian, or omnivorous diets in the studies reviewed.⁴³ Recent dietary research also suggests that providing patients with higher goals (eg, adopting a vegan diet instead of only moderate dietary changes) results in greater weight loss and maintenance.²⁶ HDRP provides training on consumption of whole plant foods, which may offer patients a unique advantage for maximizing results and higher adherence over time.

Limitations

Hands-on cooking instruction was not provided at our VAMC. The total time of the intervention was significantly less in HDRP (25 hours) than it was for the Ornish ICR program (72 hours), which may hinder long-term adherence. Without an exercise facility, we were not able to provide more detailed exercise instruction and supervised exercise.

Program Improvements Planned

There are a number of improvements that are planned for HDRP. First, the program anticipates requesting medical clearance at the telephone screening stage for self-referred patients. Second, HDRP will provide regular presentations on the program to VAMC clinics and community-based outpatient clinics, including reminders about inclusion/exclusion criteria and the referral process, and to solicit feedback on processes. Third, we hope to routinely provide education and address common questions and concerns of HCPs, including expected results. Fourth, we would like to lengthen the patient commitment to HDRP (eg, 1- to 2-year commitment to the graduate group), consistent with other HDRPs.²⁸ Fifth, we hope to further integrate technology-based components to promote behavior change/maintenance, such as automated text messaging.

Conclusions

Although our patient population was self-selected for participation, early program evaluation demonstrates high acceptability. Very few patients had ever been told about a heart disease reversing lifestyle, and we found direct-to-patient clinical outreach an effective method for launching a disease reversal program (optimally timed with HCP presentations). Furthermore, the program is adaptable to current restrictions on in-person appointments due to the COVID-19 pandemic, and much more convenient for rural veterans who live far from any VA clinic. Being able to offer sustainable health care for individuals during unexpected public health crises is critically important. Additionally, treating veterans who are most vulnerable to pandemic illness due to existing medical conditions, such as CVD, should be a high priority. Last, HDRP also may represent a novel integrated treatment for COVID-19 anxiety and secondary CVD prevention, as lifestyle habits are optimized to improve chronic diseases that elevate risk for severe COVID-19 infection and mortality, as well as including coping strategies consistent with evidence-based psychotherapies for anxiety disorders.⁴⁴

We believe that beyond the clinical benefits to patients, there is significant value and benefit added to the health care system by offering an intervention within the “disease reversal” paradigm. Efforts of the health care team to reverse a disease can be considered the highest aim of medicine and health care.⁴⁵

Acknowledgments

This work was supported by the US Department of Veterans Affairs. We give special thanks to David M. Gellerman, MD, PhD, and David W. Schafer, PsyD, for providing Mental Health Service support for initiating the Heart Disease Reversal Program, and to Joseph Giorgio, PsyD (Program Manager, Integrated Care Program) for sustaining it. We thank Amogh Bhat, MD, Chief of Cardiology, for his continued support and partnership with the Cardiology Department. We express thanks to Stephanie Mohney, RDN (Chief, Nutrition and Food Service), Amy Klotz, RDN (Supervisory Dietician), Sian M. Carr-Lopez, PharmD (Associate Chief of Pharmacy, Primary Care), and Michelle Rand, PharmD, CACP (Anticoagulation Clinical Pharmacist-Supervisor) for their staff support of this interdisciplinary program. We thank the patients and their families for their participation in the program and commitment to the lifestyle changes. We also thank the following individuals for their contributions to this program: Lisa Wagaman, RDN, Karen Soong, PharmD, Sara S. Ali, PharmD, Suzan Hua, PharmD, and Stephen Cooperman.