Relapsed ALL Patients Want CAR T-cells, Pressure Clinicians

Nancy A. Melville

June 15, 2015

VIENNA — Many patients with refractory or relapsed acute lymphoblastic leukemia (ALL), or their families, now want treatment with the engineered immune cells, even though they are still experimental, said a presenter here at the 20th Congress of the European Hematology Association (EHA).

The outlook for such patients has historically been bleak, said Adriana Balduzzi, MD, from the Clinica Pediatrica Università degli Studi di Milano Bicocca in Milan, who moderated a scientific session on the subject.

But early results with chimeric antigen receptor (CAR) modified T-cells genetically targeted to the B-cell-specific antigen CD19, which have been widely covered in the media, have raised hopes.

"The topic is definitely hot; we are talking about a potential rescue for some patients, including children, who virtually have no other chance of cure," she told Medscape Medical News.

"Many relapsed patients with acute lymphoblastic leukemia, or their families, eventually ask whether they qualify or how they can access the CAR strategy," she explained.

"I remember no other situation in which general media preceded scientific journals and created so much pressure," Dr Balduzzi said.

I remember no other situation in which general media...created so much pressure.

CAR T-cell therapy could be beneficial in a variety of scenarios, she noted, including as a consolidation therapy in refractory or nontransplanted patients, as a prophylaxis in patients who are minimal residual disease (MRD)-positive at the time of transplantation, and as a pre-emptive treatment in patients who become MRD-positive after transplantation.

"Whether the CAR approach could provide a transient remission and bridge some patients to a possible further treatment — i.e., a transplant — or cure the disease per se is still to be demonstrated, but it is certainly promising," she explained.

Data From an Adult Cohort

At the EHA meeting, two research teams reported continuing impressive results in the treatment of refractory/relapsed ALL using CAR T-cells, including in a cohort of adults.

"We found that a high complete remission rate of 87% can be achieved in adult patients with refractory or relapsed B-cell ALL," said investigator Jae H. Park, MD, from the Memorial Sloan Kettering Cancer Center in New York City.

Patients with relapses of ALL have very poor prognoses. Overall 5-year survival rates are approximately 8%, according to recent studies; for patients older than 50 years, 5-year survival rates are even lower, at approximately 3%.

Interest in immunotherapy with CAR T-cells engineered to deliver a toxic blast to antigen-expressing tumor cells has been gaining for hematologic cancers.

The data presented by Dr Park involved patients with refractory or relapsed ALL, ranging in age from 18 to 74 years, who were treated with the therapy as of March 30. Of the cohort, 39 were evaluable for toxicity assessment and 38 were evaluable for response assessment with 1 month or more of follow-up.

Twenty-one of the patients had morphologic disease and 18 had MRD at the time of the CAR T-cell infusion.

After the infusion, 33 of 38 patients (87%) achieved complete remission, including 26 of 32 (81%) who were negative for MRD.

The median time to complete remission was 23 days (range, 8 - 46).

Of the 20 patients with morphologic disease, 16 (80%) achieved a complete remission and 87% were negative for MRD. Of the 18 patients with MRD, 17 achieved a complete remission (94%) and 76% were negative for MRD.

With a median follow-up of 5.6 months after infusion (range, 1 to at least 38 months), the median duration of response or relapse-free survival was 5.3 months (95% confidence interval, 3 - 9). Fourteen patients remained disease-free, including 10 patients who had not undergone allogeneic hematopoietic stem cell transplantation (HSCT) and six patients with more than 12 months of follow-up.

Eleven patients proceeded to allogeneic HSCT and 14 patients relapsed during follow-up, including three who had undergone HSCT and 10 who had not.

The median overall survival duration for all patients was 8.5 months, and the overall survival rate for patients at 6 months was 59%. For those with MRD, median overall survival was 10.8 months and the overall survival rate at 6 months was 75%.

Nine (23%) patients developed severe cytokine release syndrome (CRS) and required vasopressors and/or mechanical ventilation for hypoxia. Eleven (28%) patients developed grade 3/4 neurotoxicity, and three (8%) developed grade 5 toxicity.

Of the 21 patients with morphologic disease, nine (43%) had severe CRS, eight (38%) had grade 3/4 neurotoxicity, and two (10%) had grade 5 toxicity.

And of the 18 patients with MRD, none had severe CRS, three (17%) had grade 3/4 neurotoxicity, and one (6%) had grade 5 toxicity.

"We found that the severity of CRS correlated with disease burden," Dr Park reported. "CRS was managed with an IL-6R inhibitor in four patients, with steroids in two patients, and with an IL-6R inhibitor plus a steroid in nine patients."

The researchers are making progress in predicting which patients will develop CRS. "Predominantly, it has been patients with a large burden of disease," Dr Park said.

Meanwhile, the neurologic symptoms are reversible, he added.

Pediatric Results Updated

Results from the largest cell therapy experience involving ALL reported to date were updated at the meeting by Shannon L. Maude, MD, PhD, from the Children's Hospital of Philadelphia.

This pediatric cohort has seen remarkable results. Initial results were published last year (N Engl J Med. 2014;371:1507-1517).

The update includes data on 48 patients, ranging in age from 4 to 22 years, all of whom had CD19-positive ALL.

Of this cohort, 38 patients had detectable disease prior to the infusion, 10 were negative for MRD, and 33 had relapsed after a previous stem cell transplantation.

One month after the infusion, 45 of 48 (94%) patients were in complete remission, and 42 patients had an MRD of less than 0.01% on flow cytometry.

Complete remission (85%) was achieved in 17 patients with more than 50% lymphoblasts in the bone marrow at infusion. In addition, at a median follow-up of 8 months (range, 1 - 36 months) as of April 26, 33 patients had ongoing complete remission, five of whom underwent subsequent stem cell transplantation.

Overall survival was 78% at 1 year, and 13 patients were in remission at 1 year, 10 without further therapy. Relapse occurred in 15 patients, including 10 with CD19-negative disease.

Nearly all patients (93%) developed CRS, and patients had dramatic elevations in ferritin, suggesting an association with macrophage activation syndrome.

Severe CRS requiring vasopressor or respiratory support occurred in 28% of patients. This rapidly resolved in each case, however, with patients responding to treatment with the anti-IL-6R agent tocilizumab.

Dr Park reports receiving research funding from Juno Therapeutics. Dr Balduzzi has disclosed no relevant financial relationships.

20th Congress of the European Hematology Association (EHA): Abstracts S111 and S112. Presented June 13, 2015.


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