April 4, 2017

Although most patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) experienced complete response after treatment with a type of CAR T-cell immunotherapy, pretreatment disease burden impacted the durability of the responses and long-term survival, according to data from a clinical trial presented here at the AACR Annual Meeting 2017, April 1-5.

"Adult patients with relapsed or refractory ALL have extremely poor outcomes, with the five-year survival rate being less than 10 percent. Therefore, there is a clear need to develop effective therapy for these patients," said Jae Park, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center (MSKCC) in New York.

"To this end, we and other groups have developed and tested CD19-specific CAR T-cell therapy [19-28z CAR T-cell therapy] and have reported encouraging results, with high initial complete response rates in patients with B-ALL. However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients," Park noted.

Park and colleagues, therefore, retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy to identify patients who benefited the most from this therapy. All of the 51 adult patients in this trial had relapsed or refractory B-ALL after one or more conventional multiagent chemotherapy.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into two cohorts those who had minimal residual disease (MRD) with less than 5 percent blast cells in bone marrow (20 patients), and those who had morphologic disease, with 5 percent or more blast cells in bone marrow (31 patients).

Complete response rates in the MRD cohort and morphologic disease cohort were 95 percent and 77 percent, respectively, which was not statistically different. After a median of 18 months of follow-up, median event-free survival and overall survival could not be computed for those in the MRD cohort (because most patients were still disease-free and alive), but they were 6.3 months and 17 months, respectively, for those in the morphologic disease cohort.

The study also found that long-term survival did not improve for patients in either cohort by having a hematopoietic stem cell transplant (HSCT) after CAR T-cell therapy.

"While more patients and longer follow-up will be needed to adequately address the significance of HSTC, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients," Park noted.

"Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome," Park added.

Patients from the MRD cohort fared well in terms of side effects as well, compared with those in the morphologic disease cohort. Two of the major side effects associated with CAR T cells, cytokine release syndrome (CRS) and neurotoxicity, occurred in 42 percent and 58 percent of the patients, respectively, in the morphologic disease cohort, compared with 5 percent and 15 percent, respectively, in those from the MRD cohort. No case of cerebral edema was observed in either cohort of this study, Park noted.

A limitation of the study is that this is a retrospective analysis and the findings will need to be validated prospectively, Park said. Further, the analysis on the impact of post-CAR allogeneic HSCT was limited by a relatively small sample size in each cohort as the study was not designed to specifically answer or address that question.

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Summary

For patients with leukemia who relapse after chemotherapy, treatment options have traditionally been limited. At MSK, an experimental immunotherapy called CAR T therapy has expandedoptions for these patients. New research data presented at this years annual meeting of the American Association for Cancer Research (AACR) suggest that patients do better on the therapy when they are treated at the time of minimal residual disease.

Highlights

Like many patients who come to Memorial Sloan Kettering, Glen Blum, 31, had already received treatment at another hospital for a cancer that was proving stubbornly hard to beat.

His saga began several years ago, when lingering back pain led to a blood test, a biopsy, and eventually a diagnosis of acute lymphoblastic leukemia, or ALL. This aggressive cancer, which grows in the bone marrow, had already damaged several of his vertebrae. He received conventional treatment with both chemotherapy and radiation, which helped for a while. But as is often the case with ALL, the cancer came roaring back. And when it did, it was resistant to further treatment with conventional drugs.

Thats when Mr. Blums doctor recommended that he enroll in a clinical trial of an experimental immunotherapy treatment at MSK. The goal of that treatment, called chimeric antigen receptor (CAR) T cell therapy, would be to shrink his cancer down to a point where he would be eligible for a potentially life-saving bone marrow transplant.

The way they explained itto me is that the treatment would get my own immune cells to see the cancer cells as foreign and eliminate them, says Mr. Blum, who lives in East Harlem in New York City. Then the bone marrow transplant was a secondary step so that I wouldnt grow more cancer cells.

The treatment would get my own immune cells to see the cancer cells as foreign and eliminate them.

Historically, a bone marrow transplant is often a leukemia patients last, best hope for a cure once initial therapy has failed. But the procedure is not without significant risks. To receive new bone marrow, patients must first have their existing bone marrow destroyed with high-dose chemotherapy or radiation. Because the bone marrow is what produces blood cells including the white blood cells that make up the immune system patients are vulnerable to infections while the new bone marrow grows. There is also the risk that immune cells from the donor marrow will start to attack the bodys healthy cells, a dangerous complication called graft-versus-host disease.

But what if it were possible for patients to receive CAR T cell therapy earlier, before a relapse? Would outcomes for these patients be better? And might they be able to forgo a bone marrow transplant altogether?

On April 3, at the AACR annual meeting, MSK physician-scientist Jae Park presented research that speaks directly to these questions. Dr. Park and his colleagues took a retrospective look at all adult patients with relapsed or refractory ALL treated with CAR T cells at MSK 51 patients in all. They wanted to understand who benefits the most from this experimental treatment. For example, does the amount of leukemia a person has at the time of CAR T therapy influence how long that person remains free of disease or how severe the side effects are?

To get at these questions, the team divided those 51 patients into two groups: those with minimal residual disease (MRD, defined as less than 5% of cancer cells in the bone marrow at the time of CAR therapy) and those with obvious morphologic disease (MD, defined as 5% or greater cancer cells in the bone marrow). They then performed statistical analyses on the two groups to determine whether they differed in terms of length of survival and severity of side effects.

What they found was that, indeed, there was a significant difference in outcomes between the two groups. Although both groups initially experienced deep regressions leading to a high rate of complete responses, patients in the MRD group lived longerand hadless toxicity compared with those in the MD group. (After an average of 18 months of follow-up, most of the MRD patients werestill alive and free of disease, while the MD patients had a median survival of 17 months; the rate of a life-threatening side effect called cytokine release syndrome was 5% for MRD patients versus 42% for MD patients.)

According to Dr. Park, the results of this study provide strong support for administering CAR T cell therapy soon after initial chemotherapy, when a patient has minimal residual disease, rather than waiting until a patient relapses. The data from this study, he says, indicate that the CAR T cell therapy is likely to be both more effective and less toxic in the earlier setting. A prospective study to test this hypothesis is currently being planned.

Our ultimate goal is to cure the disease with as little therapy as possible and with the minimum of toxicity.

Another suggestive finding though one that needs to be interpreted with caution, given the small sample size was that receiving a BMT after the CAR T therapy did not seem to improve outcomes in either group of patients. This raises the possibility that CAR T therapy might serve as a final or destination therapy, rather than as a bridge to transplant as it is typically used.

Our ultimate goal is to cure the disease with as little therapy as possible and with the minimum of toxicity, Dr. Park says. A bone marrow transplant is currently the only proven curative treatment for patients with relapsed or refractory ALL. But at the same time, its a pretty toxic therapy, and carries a mortality rate anywhere from 15% to 25%. So if we could use CAR T cell therapy to treat the disease while sparing at least some patients the risks of transplant, that would be a big improvement.

Glen Blum and his fiance, Ashley

For Mr. Blum, there was never really a question that he would go for the transplant, though he admits there was a point after the CAR T cell therapy when he considered his options.

Hearing that your cancer is at zero feels like a victory, he said. It feels like, Oh great, Im done.But then when I thought about all I went through to get to that point all the rounds of chemo and radiation, the hospital stays, the experimental treatment to not go the last mile just didnt feel right.

Yet Mr. Blums experience with bone marrow transplantation indicates why doctors are eager get to a point at which they can safely avoid it. About a month after the transplant, he got an infection that led to a severe case of pneumonia.

I was in the ICU, and honestly, it was a really scary time, Mr. Blum says. The doctorstold my mother not to leave the hospital. They were worried I might not make it.

According to Dr. Park, the decision to recommend a BMT or not becomes a question of weighing different factors, including the number of previous treatments, the characteristics of the disease, the risks of the transplant, the risk of relapse, and the age of the patient.

These are the practical conversations were having with patients every day, he says. And while Im not suggesting by any means that weve answered the question definitively, this study raises the possibility that at least for some patients CAR therapy could be an end point.

In May, it will be one year since Mr. Blum had his bone marrow transplant. Though he still has some back pain, he says he is feeling much better. Hes since gotten engaged, and he and his fiance, Ashley, are planning a trip to Jamaica in June assuming doctors give him the all-clear before then.

He says he has no regrets about the treatment he received, despite the difficulties. He always felt very well cared for at MSK.

That hospital is a piece of heaven, Mr. Blum says. Everyone there, including Dr. Park, has a heart three times the size of normal.

Link:
#AACR17: Study Explores Best Time to Give CAR T Cell Therapy - Memorial Sloan Kettering Cancer Center (blog)

Bangladeshi activist and city-based medical centres collaborate to provide life-saving treatment for the three patients.

A Navi Mumbai-based treatment centre used stem cell therapy for the first time on three Bangladeshi patients suffering from an incurable muscular dystrophy.

The trio have been suffering from a rare disease called Duchenne Muscular Dystrophy, which causes progressive muscle degeneration, since birth. The disease limits the lifespan of the patient to just 30 years.

The doctors took stem cells from the patients bone marrow in the hip bone, processed it and injected it back into their bodies. The coordinator between the patients and the treating centre, Avantika Patil said, The patients are also undergoing physiotherapy and occupational therapy while we wait for the results of the procedure to show.

The treatment was made possible by the efforts of a Bangladeshi activist, Noor Khan, a Mumbai-based organisation, Meditourz, which worked in collaboration with a brain and spine institute from Navi Mumbai, NeuroGen.

It was NeuroGen which learnt about the three patients from an article in the international media and offered to treat their disease.

Of the three patients, the youngest, Shorab (8) has a mild disorder. This early medical intervention is expected to make his life less painful. However, the other two patients, Abdus (24) and Rahinul (14) are at a progressive stage.

Their father, Tofazzal Hossain, had even sought mercy killing from Bangladesh government for the duo as he could not afford the cost of their treatment. The travel arrangements were made in coordination with the Indian government. Free round-trip tickets were offered to six persons the patients and their caretakers who accompanied them to Mumbai from Kolkata, by Air India.

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Bangladeshi patients treated with stem cell therapy in city - Mumbai Mirror