INHERTU-TUCATINIB NEAR APPROVAL BY EMA

 The drug review panel for the European Medicines Agency (EMA) has endorsed the approval of several cancer therapies.

The Committee for Medicinal Products for Human Use (CHMP) has recommended granting conditional marketing authorization for trastuzumab deruxtecan (Enhertu) for the treatment of metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer.

Trastuzumab is a monoclonal antibody–drug conjugate that binds to HER2, disrupting signaling and mediating antibody-dependent cell-mediated cytotoxicity. It was reviewed under the EMA's accelerated assessment program and is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more anti-HER2-based regimens.

The second drug is fedratinib (Inrebic), which received a positive opinion for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocythemia myelofibrosis who are JAK-inhibitor naive or who have been treated with ruxolitinib (Jakafi).

The active substance is fedratinib, a protein kinase inhibitor with activity linked to the selective inhibition of JAKs involved in the signaling mediation of several cytokines and growth factors that play a role in hematopoiesis and immune function.

Marketing authorization under exceptional circumstances was recommended for moxetumomab pasudotox (Lumoxiti) for the treatment of relapsed or refractory hairy cell leukemia in patients who have already received at least two systemic therapies, including treatment with a purine nucleoside analogue.

The agent's active substance is moxetumomab pasudotox, a CD22-targeted immunotoxin that is designed to direct the cytotoxic action of the truncated Pseudomonas exotoxin to cells that express the CD22 receptor.

The most common adverse events reported are peripheral edema, nausea, fatigue, headache, and pyrexia. Identified risks include hemolytic uremic syndrome and capillary leak syndrome.

The committee also recommended granting marketing authorization to selpercatinib (Retsevmo), which is indicated for the treatment of cancers with a rearranged during transfection (RET) gene fusion. These cancers include RET-fusion-positive non–small cell lung cancer (NSCLC), RET-fusion-positive thyroid cancer, and RET-mutant medullary thyroid cancer (MTC).

Associated benefits observed with selpercatinib are the objective response rate and response duration in previously treated patients with RET-fusion-positive NSCLC or thyroid cancer and RET-mutant MTC. The most common reported side effects are increased aspartate transaminase level, increased alanine transaminase level, decreased lymphocyte count, dry mouth, increased creatinine level, diarrhea, fatigue, edema, and hypertension.

The CHMP also gave a positive opinion regarding tucatinib (Tukysa), which is indicated for use in combination with trastuzumab and capecitabine for the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have received at least two prior anti-HER2 treatment regimens.

Associated benefits are the drug's ability to increase progression-free survival and overall survival, including for patients with metastases. The most common observed side effects are diarrhea and increased liver enzyme levels.

New Generics

The CHMP has also given a positive recommendation for four generic medicines to be used in cancer care.

The first is lenalidomide Krka (KRKA, d.d., Novo mesto), which is recommended for the treatment of multiple myeloma and follicular lymphoma.

Lenalidomide Krka is a generic of Revlimid, which has been authorized for use in the European Union for over a decade. The generic formulation has demonstrated satisfactory quality and bioequivalence to the reference product. Lenalidomide Krka is indicated for use as monotherapy in maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplant; as combination therapy with dexamethasone or bortezomib and dexamethasone or melphalan and prednisone in previously untreated patients who are not eligible for transplant; and in combination with dexamethasone for patients who have received at least one prior therapy.

For previously treated adult patients with grade 1–3a follicular lymphoma, lenalidomide Krka is to be used in combination with rituximab (Rituxan).

Lenalidomide Krka d.d. has the same indications as lenalidomide Krka with the addition of myelodysplastic syndromes for adult patients with transfusion-dependent anemia at low risk or intermediate risk with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

Lenalidomide Krka d.d. Novo mesto has the same indications as lenalidomide Krka d.d. with the addition of mantle cell lymphoma, for which it is indicated for relapsed or refractory disease.

The CHMP has also adopted a positive opinion and recommended granting marketing authorization for Sunitinib Accord (Accord Healthcare SLU), the generic of Sutent, which has been marketed in the European Union since 2006. Studies have demonstrated that the generic product has satisfactory quality and bioequivalence to the reference product.

It is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumor in adults after failure of imatinib treatment due to resistance or intolerance; advanced/metastatic renal cell carcinoma in adults; and unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors with disease progression in adults.

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CAR-T CELLS FOR FOLLICULAR LYMPHOMA

 For the first time, a chimeric antigen receptor (CAR) therapy has yielded a high response rate among patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL), including patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL).

The new results come from the ZUMA-5 trial with axicabtagene ciloleucel (axi-cel; Yescarta), in which responses were seen in more than 90% of trial participants.

The results could lead to new indication for the product, which has already been approved for the treatment of large B-cell lymphoma for patients who experience disease progression with at least two prior lines of therapy. The approval was based on data from the ZUMA-1 trial.

The new data were reported at the American Society of Hematology (ASH) 2020 Annual Meeting by Caron Jacobson, MD, the Dana-Farber Cancer Institute, Boston, Massachusetts.

She said the data showed response rates of more than 90% among patients with iNFL, including patients with FL and MZL.

Data from ZUMA-5 in iNHL were more favorable than those seen in ZUMA-1 for patients with aggressive lymphomas.

"We were very impressed with the magnitude of the responses, and also the durability," Jacobsen said in an institute statement. "This treatment has meaningfully impacted high-risk patients with these diseases. I was also struck early on by how favorable the safety profile was compared to what we've been seeing in the fast-growing lymphomas."

Approached for comment, Gary Schiller, MD, professor of medicine and director of the Hematological Malignancy/Stem Cell Transplant Program at the David Geffen School of Medicine, University of California, Los Angeles, agreed.

"I found the results surprising, because the adverse event profile is more favorable than that seen for the other aggressive lymphomas. Even response rates are better than the ones seen in aggressive disease, such as ALL [acute lymphoblastic leukemia] and DLBCL [diffuse large B-cell lymphoma]," Schiller told Medscape Medical News.

In clinical practice, Schiller has used CAR T-cells for patients with diffuse large B-cell lymphoma, an indication specified on the current product labeling. He noted that prior authorization is required for patients with commercial insurance, but he said his patients have never been denied access. For these patients, he typically uses axi-cel after the second relapse.

Schiller pointed out that CAR T-cell therapy is evolving and that the toxicity profile of the therapy needs improvement, but he noted that "in this study, there was a low rate of grade 3/4 cytokine release syndrome — a more daunting side effect of CAR T-cell therapy."

"If approved for this indication [iNHL], I would consider using it," Schiller said.

Although other options are available for patients with iNHL, such as Bruton tyrosine kinase inhibitors, conventional chemoimmunotherapy, and PI3K [phosphatidyl inositol-3 kinase] inhibitors, Schiller noted that two thirds of patients have already received more than three prior lines of therapy and no other treatment options may be available.

"The study has convincingly demonstrated the unprecedent responses of CAR T-cells on heavily pretreated patients with FL, specifically for those who have failed multiple regimens," Henry Fung, MD, chair of the Department of Bone Marrow Transplant and Cellular Therapies, Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News. He predicted that axi-cell "will become a very important option for these patients."

Fung noted that despite the efficacy of CAR T-cell therapy, very few patients with advanced refractory disease are likely to experience a long-lasting response. "Now, we need studies to define the best time for this groundbreaking treatment and who will benefit the most. The ultimate goal should be achieving a durable remission and possibly cure," Fung told Medscape Medical News.

Ongoing clinical trials are exploring earlier use of CAR T-cells, Jacobsen commented. For example, CAR T-cell therapy is being tested in the second-line setting against salvage chemotherapy or autologous stem cell transplants for patients with high-risk disease.

Some results have been reported. For example, results of ZUMA-12 that were presented at the ASH meeting show that for patients with high-risk large B-cell lymphomas who did not experience a complete response to two cycles of an anti-CD20 monoclonal antibody and an anthracycline-containing regimen did experience a response to CAR T-cell therapy. This study will provide insights into the efficacy of CAR T-cells in the pseudo first-line setting, Jacobsen commented.

ZUMA-5 Study Details

ZUMA-5 was a multicenter, single-arm, phase 2 study that involved patients with relapsed or refractory iNHL who had received at least two prior lines of therapy.

Data were reported for 124 patients with FL and 22 patients with MZL. All patients had received CAR T-cells that had been made individually for each patient. About half the patients had bulky disease; 64% had received at least three prior lines of therapy; and 23% had received prior autologous stem cell transplants.

The median follow-up for efficacy was 17.5 months. The efficacy data for 104 patients (FL: 84 patients; MZL: 20 patients) showed an overall response rate of 92% (FL: 94%; MZL: 85%) and a complete response (CR) rate of 76% (FL: 80%; MZL: 60%). High response rates were seen across all groups of patients regardless of tumor burden, number, and type of prior therapies.

The 12-month duration of response was 71.7% for all patients and 77% for patients with FL. It was not evaluable for those with MZL.

One-year progression-free survival was 73.7%, and 1-year overall survival was 92.9%.

Safety data were reported for all 146 patients who received CAR T-cells. Most of the grade ≥3 side effects were cytopenias (70%) and infections (16%). Three patients died; one death, from CRS, was attributed to axi-cel.

CRS was seen in 82% of patients (grade ≥3 CRS: 7%). The median time to onset was 4 days, and the median duration was 6 days. At data cutoff, no patient had ongoing CRS.

Grade ≥3 neurologic events were reported in 15% of patients with FL and in 41% of patients with MZL.

Response rates were slightly higher and rates of adverse events were slightly lower among patients with FL than among those with MZL, Jacobson noted.

The ZUMA-5 trial was sponsored by Kite/Gilead, manufacturer of axi-cel. Jacobson has disclosed no relevant financial relationships. Schiller reported honoraria/research funding/consultancy/stock ownership from AbbVie, Actinium, Actuate, Agios Pharmaceuticals, Amgen, AROG, Astellas, Bristol-Myers Squibb, Celgene, Constellation Pharmaceuticals, Daiichi Sankyo, Deciphera, Delta-Fly, Forma, FujiFilm, Gamida, Genentech, Geron, Gilead, Glycomimetics, Incyte, Jazz Pharmaceuticals, J&J, Juno, Karyopharm, Kite/Gilead, Mateon Therapeutics, MedImmune, Onconova, Pfizer, RegImmune, Samus, Sangamo Therapeutics, Sanofi, Stemline, Takeda, Tolero, and Trovagene. Fung reported being on the speakers' bureaus of Jansen Oncology and Celgene/BMS.

American Society of Hematology (ASH) 2020 Annual Meeting: Abstract 700. Presented December 7, 2020.

Medscape Medical News © 2020 

HEMATOLOGY PRACTICE CHANGING UPDATES

 

Instead of flying out to San Diego in California and soaking up a bit of sunshine in between listening to new research presentations, hematologists from around the world will be glued to their computer screens next weekend, tuning into the 62nd American Society of Hematology annual meeting.  

Like many other conferences this year, the ASH meeting will be virtual because of the continuing COVID-19 pandemic, although the dates remain the same: December 5-8.  

This is the premier hematology event of the year, and the largest hematology conference in the world, with around 3500 abstracts presented this year, commented Aaron T. Gerds, MD, chair of ASH's Committee on Communications.

Ruxolitinib in Chronic GvHD

"One of the things that people come to ASH for is to hear about practice-changing clinical trials, and this year is no exception," said ASH secretary Robert Brodsky, MD.

In a preview webinar, he highlighted four abstracts that offer opportunities to change practice and revamp the current standards of care.

One clinical trial that is "almost certainly a practice changer," he said, is the REACH 3 study (abstract 77) of the JAK-inhibitor ruxolitinib (Jakafi, Incyte) in patients with chronic graft-versus-host disease (GvHD) after a stem cell transplant.

"This has been really hard to treat in patients undergoing allogeneic bone marrow transplants," said Brodsky. "Steroids are the first-line treatment, but after that, nothing else has shown any improvement, and even steroids don't work that well."

There is currently no approved second-line therapy for chronic forms of GvHD, he emphasized. 

The main endpoint of the trial was overall response rate, which was doubled with ruxolitinib compared to the best available therapy (50% vs 25%).

"This is the first successful phase 3 trial for chronic GvHD," Brodsky commented.  

Transplants for Older Patients With MDS

Transplant offers the only curative option for myelodysplastic syndromes (MDS), but typically this option is offered to younger patients because benefits for older adults have not been well-defined, Brodsky noted.

New data from a clinical trial conducted in patients with advanced MDS aged 50-75 years (abstract 75) offers the most definitive evidence to date that allogeneic hematopoietic cell transplantation (AHCT) can significantly improve outcomes for older adults.  

It's clear that transplant is the standard of care in younger patients, Brodsky commented, and although there is a trend of offering it to older patients, some are not getting referred and instead are being offered palliative care. "The thinking is that bone marrow transplant would be too toxic in this age group," he said. "But what is very clear here is that, in an intent-to-treat analysis, there was a significant survival advantage — 48% versus 27% at 3 years for transplantation — and it was seen across all subgroups."

Subcutaneous Daratumumab

New data on a subcutaneous formulation of daratumumab (Darzalex, Janssen), which is usually given by intravenous infusion, will be presented from the APOLLO trial (abstract 412) in patients with relapsed/refractory multiple myeloma.

Patients who received subcutaneous daratumumab combined with pomalidomide and dexamethasone had a 37% reduction in disease progression or death compared to those who received pomalidomide and dexamethasone alone.

"From previous years we've learned that daratumumab has had a major impact on outcomes in multiple myeloma," said Brodsky. "The nice thing about the subcutaneous formulation is that it can be administered quickly and in an outpatient setting, which is especially important in the COVID era."  

Negative Data With Tranexamic Acid

The fourth abstract highlighted by Brodsky is a negative study, but its findings can help guide clinical practice, he said. The a-TREAT study (abstract 2) showed that, despite being routinely used in the clinical setting, tranexamic acid does not prevent bleeding when administered prophylactically to severely thrombocytopenic patients undergoing treatment for hematologic malignancies.

"They found absolutely no difference in bleeding or need for transfusion," said Brodsky. "What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia."

'Very Exciting' News About Gene Therapy

Brodsky also highlighted several late-breaking abstract that will be presented at the meeting.

In particular, the first data on a gene therapy for hemophilia B (abstract LBA-6) are "very, very exciting," he said. The HOPE-B trial showed a 96% response rate among patients with hemophilia B who were treated with etranacogene dezaparvovec, an investigational gene therapy comprised of an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX.

Brodsky pointed out that this was a large trial with 54 patients, but importantly, it included patients with pre-existing anti-AAV5 neutralizing antibodies. "About 40% of patients have naturally occurring antibodies to AAV5 and they have been excluded from previous trials because it was thought they wouldn't take the vector," said Brodsky. "But only one patient didn't get a response."

Following a single dose of etranacogene dezaparvovec, Factor IX activity increased into the mild-to-normal range without the need for prophylactic immunosuppression. Treated patients were able to discontinue prophylaxis and bleeding was controlled in most of the cohort.

"This is a big advance and we are getting very close to the point where gene therapy is going to be standard of care for some forms of hemophilia," said Brodsky. However, he added that "we will still need to see more patients and have longer follow-up."

He added that, with time, the technology behind gene therapy will probably become less expensive and more accessible to more patients, which will help become a standard of care.

This is also the hope for the technology behind chimeric antigen receptor T-cell (CAR-T) therapy, he added. At present, this cellular therapy is manufactured individually for each patient and is very expensive, but work on "off-the-shelf" products is underway. This topic will be explored during the presidential symposium, entitled, "Universal Donor Solutions in Hematology."

New data on one of the currently available CAR-T cell products will be presented at the meeting. The phase 2 ZUMA-5 trial showed that axicabtagene ciloleucel (Axi-Cel) may be a viable option for some patients with high-risk non-Hodgkin lymphoma who have not responded to standard treatments (abstract 700).

At a median follow-up of almost 18 months, 92% of participants achieved an objective response and 78% achieved a complete response to the treatment. By 12 months, 72% were still in response, and at 17.5 months, 64% were still in response.

"We were very impressed with the magnitude of the responses, and also the durability," said senior study author Caron Jacobson, MD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, in a press release. "I was also struck early on by how favorable the safety profile was compared to what we've been seeing in the fast-growing lymphomas, such as large B cell lymphoma."

Race and Bloods Cancers

ASH president Stephanie Lee, MD, MPH, highlighted several abstracts on disparities that will be presented at the meeting. One of these, which is to be presented during the plenary session, is an analysis of patient survival in acute myeloid leukemia (AML) (abstract 6).

It found that "self-reported race was the best indicator of survival," noted Lee.

Overall survival at 3 years was 41% in White patients versus 32% in Black patients, a difference that was highly significant, she noted.

Part of the study also evaluated patients who were all on the same chemotherapy protocol, "so there was no effect of different treatment, since they were on therapy determined by the trial," said Lee.

Black patients were less likely to have normal cytogenetics compared with White patients (38% vs 51%; P = .01) and had a lower frequency of prognostically favorable NPM1 mutations (25% vs 38%; P = .04), but higher frequencies of spliceosome gene mutations (24% vs 12%; P = .009). Thus, the results showed race was an independent prognosticator of poor survival in AML, aside from established molecular markers.

A special scientific session on race will be held on December 5, Lee noted. While other abstracts consider race from the patient side, this session will focus on the scientist's side, she explained, and address questions such as: "What are the implications of diversity and racism? And how does that impact scientists who are from underrepresented minorities?" 

COVID-19 and Blood Disorders

Lee also highlighted a study (abstract 215) that analyzed emerging data from the ASH Research Collaborative COVID-19 Registry for Hematology, which was developed to look at outcomes of COVID-19 infection in patients with underlying blood disorders.

An analysis of data from 250 patients at 74 sites around the world found that overall mortality was 28%. "This supports the emerging consensus that patients with hematologic malignancies experience significant morbidity and mortality from COVID-19 infection," say the authors.

"We do need real-world data to see how SARS-CoV-2 is affecting our patients with hematologic diseases or those who don't have a hematologic disease but who are then infected with the coronavirus and develop a hematologic problem like blood clots," said Lee.

"More data will be coming in, but this is a good example of trying to harness real-world information to learn things until we have more controlled trials."

'Fireside Chat' With Fauci

COVID-19 will be on the agenda for a special session billed as a "fireside chat" with Anthony Fauci, MD, of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

"This will be kicking off our meeting on Saturday morning," said Lee.

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NO CHEMO OPTION FOR ALL

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, up-front chemo-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, "impressive" survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, "60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab," lead researcher Robin Foà, MD, from Sapienza University of Rome, in Italy, told Medscape Medical News.

"The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity," Foà added.

"I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age," Foà said.

The results of the study were published October 22 in The New England Journal of Medicine.

"Innovative" and "Highly Successful"

This "innovative" chemo-free approach proved "highly successful" with "surprisingly" few toxic effects, writes Dieter Hoelzer, MD, PhD, University of Frankfurt, Germany, in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24 – 82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 μg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab — to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival (DFS) was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [ie, IKZF1plus]).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients, neutropenia in four patients, persistent fever in two patients, and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is "remarkable," Hoelzer writes in his editorial. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant — "a consequence that is avoided with targeted therapy."

Unanswered Questions

"Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment," editorialist Hoelzer notes.

He says other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

"If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials," Hoelzer concludes.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome. Disclosures for the authors and the editorialist are available with the full article at NEJM.org.

N Engl J Med. Published October 22, 2020. Abstract, Editorial

PEMBROLIZUMAB FOR HODGKIN LYMPHOMA

On October 14, the U.S. Food and Drug Administration (FDA) extended the approval of pembrolizumab (Keytruda) for the following indications:  

• Adult patients with relapsed or refractory classical Hodgkin lymphoma
• Pediatric patients with refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma that has relapsed after two or more lines of therapy.

KEYNOTE-204

Approval was based on KEYNOTE-204, a phase III, randomized, open-label trial in 304 adult patients with relapsed or refractory classical Hodgkin lymphoma treated with at least one prior multiagent regimen. Patients were randomly assigned 1:1 to receive either pembrolizumab at 200 mg every 3 weeks or brentuximab vedotin at 1.8 mg/kg every 3 weeks for up to 2 years. Efficacy was based on progression-free survival per blinded independent central review assessment.

Progression-free survival was statistically significantly longer in the pembrolizumab arm. The median progression-free survival was 13.2 months (95% confidence interval [CI] = 10.9–19.4) in the pembrolizumab arm and 8.3 months (95% CI = 5.7–8.8) in the brentuximab vedotin arm, with a hazard ratio of 0.65 (95% CI = 0.48–0.88, P = .0027).

Serious adverse reactions occurred in 30% of the patients who received pembrolizumab. Adverse reactions in ≥ 20% of pembrolizumab recipients included upper respiratory tract infection, musculoskeletal pain, diarrhea, cough, pyrexia, fatigue, and rash. Serious adverse reactions in ≥ 1% of patients included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Thirty-eight percent of patients had adverse reactions requiring systemic corticosteroids, including pneumonitis in 11%.

The recommended pembrolizumab dose for patients with lymphoma is 200 mg every 3 weeks or 400 mg every 6 weeks intravenously for adults, or 2 mg/kg (up to 200 mg) every 3 weeks intravenously for pediatric patients, for up to 2 years.

A NOVEL REGIMEN FOR ELDERLY WITH AML

On October 16, the U.S. Food and Drug Administration (FDA) granted regular approval to venetoclax (Venclexta) in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed acute myeloid leukemia (AML) in adults age 75 or older or who have comorbidities precluding intensive induction chemotherapy. Venetoclax was initially granted accelerated approval for this indication in November 2018.

Efficacy was confirmed in two randomized, double-blind, placebo-controlled trials in patients with AML described above.

VIALE-A and VIALE-C

In VIALE-A, patients were randomly assigned to receive venetoclax plus azacitidine (n = 286) or placebo plus azacitidine (n = 145). Efficacy was established based on an improvement in overall survival. The median overall survival was 14.7 months (95% confidence interval [CI] = 11.9–18.7) in patients treated with venetoclax plus azacitidine compared to 9.6 months (95% CI = 7.4­–12.7) in those receiving placebo plus azacitidine (hazard ratio [HR] = 0.66, 95% CI = 0.52–0.85, P < .001). Patients treated with venetoclax plus azacitidine also demonstrated an improvement in complete remission rate: 37% (95% CI = 31%–43%) vs 18% (95% CI = 12%–25%).

In VIALE-C, patients were randomly assigned to receive venetoclax plus low-dose cytarabine (n = 143) or placebo plus low-dose cytarabine (n = 68). Efficacy was based on complete remission rate and duration of complete remission. The complete remission rate in the venetoclax plus low-dose cytarabine arm was 27% (95% CI = 20%–35%) with a median duration of 11.1 months (95% CI = 6.1–not reached) compared to 7.4% (95% CI = 2.4%–16%) with a median duration of 8.3 months (95% CI = 3.1–not reached) in those receiving placebo plus low-dose cytarabine. Venetoclax plus low-dose cytarabine did not significantly improve overall survival vs placebo plus low-dose cytarabine (HR = 0.75, 95% CI = 0.52­–1.07, P = .114).

The most common adverse reactions seen in patients treated with venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine (≥ 30% in any trial) were nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, musculoskeletal pain, dizziness, cough, oropharyngeal pain, and hypotension.

FIRST MAINTENANCE THERAPY FOR AML

The US Food and Drug Administration (FDA) has approved an oral form of azacitidine (Onureg) for use as maintenance therapy for patients with acute myeloid leukemia (AML) who have achieved a first complete remission.

The approval extends to patients who have achieved complete remission with incomplete blood count recovery following intensive induction chemotherapy and who are unable to complete intensive curative therapy.

The approval was based on data from the QUAZAR AML-001 trial, which showed that oral azacitidine significantly improved overall survival when compared to placebo.

"It's not too hard to get these patients into remission," Harry P. Erba, MD, PhD, director of the Leukemia Program at the Duke Cancer Institute, Durham, North Carolina, told Medscape Medical News last year, when these results were first presented at the 2019 annual meeting of the American Society of Hematology. "The problem comes in keeping them in remission."

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne, Australia, said.

"Oral azacitidine represents a new therapeutic standard for patients with AML in remission," he said.

Azacitidine is a hypomethylating agent that incorporates into DNA and RNA. It has long been used as an injectable therapy for the treatment of myelodysplastic syndromes.

The approval of the new oral formulation for the new indication of AML "is the culmination of over a decade of research and 13 preclinical and clinical trials," said Giovanni Caforio, M.D., chairman and chief executive officer of Bristol-Myers Squibb, in a statement.

QUAZAR Results 

The QUAZAR AML-001 trial was a phase 3, international study involving 472 patients with AML who were within achieving a first complete remission or remission with incomplete blood recovery. All patients has received intensive induction chemotherapy with or without consolidation treatment, per investigator preference prior to study entry, and were not candidates for hematopoietic stem cell transplant at the time of screening.

Patients were randomly assigned to receive either oral azacitidine 200 mg daily on days 1 to 14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or underwent transplant.

At a median follow-up of over 41.2 months, the median overall survival was significantly longer for patients who received oral azacitidine, at 24.7 months vs 14.8 months for those who received placebo (P < .0009; hazard ratio [HR], 0.69).

Relapse-free survival was also significantly prolonged to 10.2 months for patients who received oral azacitidine vs 4.8 months for those who received placebo (HR, 0.65; P < .0001).

Serious adverse reactions occurred in 15% of patients who received azacitidine. Events that occurred in ≥2% of patients include pneumonia (8%) and febrile neutropenia (7%). There was one fatal event.

The most common adverse reactions were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%) arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%) and pain in extremity (11%, 5%). Permanent discontinuation because of an adverse reaction occurred in 8% of patients.

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PET DIRECTD THERAPY FOR LIMITED DLBCL

As reported in the Journal of Clinical Oncology by Daniel O. Persky, MD, and colleagues, the phase II Intergroup National Clinical Trials Network Study S1001 has shown good outcomes with positron-emission tomography (PET)-directed therapy in patients with limited-stage diffuse large B-cell lymphoma (DLBCL). 

As stated by the investigators, “Diffuse large B-cell lymphoma presents as a limited-stage disease in 25% to 30% of patients, with better overall survival than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of PET-directed treatment approaches, we designed a National Clinical Trials Network study to improve outcomes and decrease toxicity.”

Daniel O. Persky, MD

Study Details 

S1001 enrolled previously untreated patients with nonbulky (< 10 cm) stage I/II CD20-positive DLBCL. With a change in World Health Organization classification during the study period, new categories of high-grade B-cell lymphoma with or without MYC and BCL2 or BCL6 rearrangements were also eligible. The study was activated in July 2011, with accrual completed in June 2016.

A total of 132 eligible patients received three cycles of standard R-CHOP treatment given every 3 weeks, consisting of rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m², vincristine at 1.4 mg/m² (maximum 2 mg), and prednisone at 100 mg per day for 5 days. Patients underwent interim PET between day 15 and 18 of cycle 3, with findings centrally reviewed in real time.

Patients with negative results received one additional cycle of R-CHOP. Those with positive results received 36 Gy of involved-field radiation therapy (IFRT) and an additional boost to fluorodeoxyglucose (FDG)-avid areas of up to 9 Gy within 5 weeks of cycle 3 of R-CHOP. At 3 to 6 weeks after completion of IFRT, patients received ibritumomab tiuxetan radioimmunotherapy with rituximab at 250 mg/m² on day 1 and days 7, 8, or 9 and ibritumomab tiuxetan at 0.4 mCi/kg on days 7, 8, or 9 after rituximab.

A final PET scan was performed 12 weeks after completion of treatment. Patients were followed with examination and testing, including computed tomography scans every 6 months for the first 2 years and then annually for up to 7 years or until death. 

Treatment Outcomes

Of the 132 eligible patients, 128 underwent interim PET. Of these, 14 patients (11%) had positive findings—2 refused radiation and 12 received IFRT followed by ibritumomab tiuxetan. Of the 12 who received treatment, 8 converted from partial response in germinal center B-cell (GCB) disease to complete response, and 4 had partial response. Overall, compete response was achieved in 92% of patients, partial response in 4%, and stable disease in 1%, with four patients (3%) being unevaluable.  

Over a median follow-up of 4.92 years (range = 1.1–7.7 years), disease progression occurred in six patients, and three patients died from lymphoma. Of the six patients who experienced progression, four were interim PET–negative and received R-CHOP x 4, one was interim PET–positive but declined radiation, and one went off treatment after one cycle of R-CHOP. One patient had progression in the central nervous system. No cases of primary refractory disease were observed. A total of 11 patients died as a result of nonlymphoma causes; the median age of these patients was 80 years (range = 56–86 years).

Among all patients, estimated 5-year progression-free survival was 87% and 5-year overall survival was 89%, including progression-free survival rates of 86% vs 89% and overall survival rates of 85% vs 91% among interim PET­–positive vs interim PET–negative patients. Histology was not associated with outcome, whereas associations were observed for stage-modified International Prognostic Index (smIPI) score, cell of origin, and double protein expression (DPE) status.

Progression-free survival at 5 years was:

• 97% for smIPI of 0
• 86% for smIPI of 1 to 2
• 30% for smIPI of 3
• 95% for GCB disease
• 72% for activated B-cell disease
• 49% for unclassifiable disease
• 89% for patients with negative DPE status
• 70% for patients with positive DPE status.

Adverse Events

The most common grade 3 or 4 adverse events among all patients were decreased neutrophil count (31%), decreased white blood cell count (27%), decreased lymphocyte count (17%), febrile neutropenia (10%), anemia (8%), and decreased platelets (8%). In addition, two patients (2%) had grade 3 lung infection, three (2%) had grade 3 urinary tract infection, and two (2%) had grade 3 peripheral neuropathy. Of the 12 patients who received IFRT and ibritumomab tiuxetan, 2 had grade 3 or 4 neutropenia, 3 had grade 3 or 4 thrombocytopenia, and 2 had radiation dermatitis. Adverse events led to death in two patients, due to sepsis in one and hypoxia in the other.

The investigators concluded, “With PET-directed therapy, 89% of the patients with a negative interim PET received R-CHOP x 4, and only 11% had a positive interim PET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP x 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.”

Dr. Persky, of the University of Arizona Cancer Center, Tucson, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by National Institutes of Health/National Cancer Institute grants and by Spectrum Pharmaceuticals, Inc. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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LONG TERM SAFETY OF CAR-T CELL TREATMENT

When a patient with cancer hears there isn't much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

"I was really trying to avoid a bone marrow transplant. You're playing your last card if that doesn't work. It's a pretty rough procedure," Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky — for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient's own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered "living drugs" because they expand inside the body and stick around for years — maybe for a lifetime — to fight the cancer if it tries to come back.

"I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work," Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson's T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells' expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms — so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra)Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the "aha moment" happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

"It still gives me shivers," he said. "Dr Porter said, 'Your bone marrow's completely free. We just can't find a cancer cell anywhere.' "

The remission has lasted, and it is now 10 years later.

Balancing Long-term Risks vs Benefits 

Long-term data have been accumulating for these novel therapies since Olson's treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown "remarkable" remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year's annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite's axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis' tisagenlecleucel[Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy "to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments."

"We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells," said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.

B-cell Aplasia and Risk for New Infections 

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn't overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn't stay locked up in his New Hampshire home"I took the attitude when I was diagnosed with cancer that I'm going to live my life," he said. "Quality of life to me is more important than quantity."

Neuropsychiatric Toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

"Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards," said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

"So far, we don't know what caused it," Bar said. "Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues."

Graft-vs-Host Disease 

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

"The data for CAR T cells causing GVHD really hasn't shown that it's a huge problem, although we have seen it and are continuing to monitor for it," the NCI's Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar's study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy"Any type of cancer is a very theoretical risk," Bar told Medscape Medical News."Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells."

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

"We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk," said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

"We are continuing to be vigilant in our monitoring for autoimmune disease," Shah added. "We've been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD."

Future Directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

"The theoretic risk with universal cells is that their safety profile may not be as good for long term," June commented.

Hope for the Future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

"I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive," he said. "I'd better not die of something like a heart attack!"

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

"Twenty years ago, if you had cancer, your prospects weren't nearly as good as these days. In 2010, people still didn't believe in CAR T-cell therapy," he said. "My goal always in telling my story is a message of hope."

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