Zosia Chustecka

November 29, 2016

Presentations likley to have an impact on patient care were highlighted in a press webinar held ahead of the American Society of Hematology (ASH) annual meeting. Held this year in San Diego, California, the meeting starts on Friday, December 2.

Practice-changing results that will affect the treatment of some patients with lymphoma come from three phase 3 trials, commented  Stephanie Lee, MD, MPH, secretary of ASH and a professor of medicine at the University of Washington in Seattle.

The GALLIUM study shows the new anti-CD20 antibody obinutuzumab (Gazyva, Genentech) to be superior to the older agent rituximab (Rituxan, Genentech) when used for induction and maintenance in adult patients with previously untreated follicular lymphoma (abstract 6).  The new drug, approved for follicular lymphoma earlier  this year, showed a clinically meaningful improvement in progression-free survival (PFS; 34% reduction compared with rituximab-based therapy).

The authors, headed by Robert Marcus, MD from King's College Hospital in London, United Kingdom, say  that the results support obinutuzumab with chemotherapy becoming a new standard of care in previously untreated patients with folicular lymphoma.

However, there was no difference in overall survival and side effects increased with obintuzumab when compared with rituximab.

"This trial is important because it shows us that obinutuzumab is more effective than rituzumab at prolonging time to relapse, but there are some caveats as it does look like it has higher toxicity," Dr Lee commented.

The ALCANZA  study shows that brentuximab vedotin (Adcetris, Seattle Genetics) has significantly superior clinical outcomes when compared with physician's choice of therapy (methotrexate or bexarotene) in the rare disorder of CD30-expressing cutaneous T cell lymphoma (abstract 182).

The authors, headed by Youn Kim, MD, from Stanford University School of Medicine, California, report that the clinical outcomes with brentuximab vedotin were "far superior," with highly statistically significant improvements in both overall response rates and median PFS (13.2 months vs 3 months with physician's choice of therapy).

"This trial shows that  brentuximab vedotin has significant  advantages over two commonly used treatments for this disease," Dr Lee commented. She noted that it is difficult to conduct randomized trials in rare diseases, but these investigators were able to do so and come to a fairly definitive conclusion.

The LyMa trial in younger patients with mantle cell lymphoma (MCL) shows that rituximab maintenance after autologous stem cell transplantation prolongs survival  (abstract 145).

This study, conducted in patients who were responding well after transplanation, showed that 4-year PFS and overall survival were better in patients randomly assigned to rituximab than in those receiving placebo.

The study authors, led by Steven Le Gouill, MD, PhD, from Nantes University Hospital in France, conclude that rituximab maintenace (one infusion every 2 months for 3 years) is a new standard of care for young patients with MCL.

"This trial provides good evidence that rituximab maintence improves patient outcomes after transplant," Dr Lee said. Some clinicians have already been doing this, she commented, but for those who have not, this study provides good data showing a survival advantage.

Practice-Changing Results in CLL

Dr Lee also highlighted one abstract that could change practice in the treatment of some patients with leukemia.

Final results from the German CLL M1 study (abstract 229)   show that maintenance therapy with lenalidomide (Revlimid, Celgene) after front-line chemoimmunotherapy substantially prolongs PFS in patients with high-risk chronic lymphocytic leukemia (CLL).

These patients with CLL underwent four cycles of frontline chemoimmunotherapy and had at least a partial response; they were judged to be high risk because of their cytogenetic profile or because of the amount of residual disease, Dr Lee explained. They were randomly assigned 2:1 to lenalidomide or placebo, and only 89 patients were analyzed. The aim had been 200 patients, but the study was stopped early because of the positive results at interim analysis, she said.  After a median observation time of 17.7 months, the hazard ratio for PFS was a very impressive 0.198, she commented. The median PFS in the placebo group was 14.6 months and was not reached in the lenalidomide group.

The results suggests that maintenance with lenalinomide is benefiial in these patients with high-risk CLL who have residual disease after initial chemoimmunotherapy, Dr Lee commented.

New Results With CAR T Cell Therapy

Charles Abrahms, MD, ASH president and professor of medicine at the University of Pennsylvania and Children's Hospital of Philadelphia, highlighted new research results with chimeric antigen receptor (CAR) T cell therapy.

This novel treatment approach involves taking T cells from a patient, genetically engineering them to attack antigens present on tumor cells, and then infusing them back into the body. It has shown some spectacular results in eliminating  leukemia and lymphoma, but it has also led to severe adverse reactions.

"Cytokine release syndrome and neurological symptoms do occur with this therapy, so it's not for the fainthearted, but we can usually carry patients through," Dr Abrahms commented. Usually this therapy is given within a university setting, with specially trained personel who have experience with the technology and its adverse effects.

But a new study shows that the CAR T cell technology can be brought out into the broader setting of the community, Dr Abrahms commented.

The multicenter pivotal phase 2 ZUMA-1 trial with the Kite anti-CD19 CAR T cell product (abstract LBA-6)   involved 111 patients from 22 instititions. The CAR T cells were engineered within 17 days.

The trial shows that this CAR therapy induces complete remissions in patients with refractory diffuse large B cell lymphoma, Dr Abrahms commented. The results were rather impressive, he commented, with an overall response rate of 76% and a PFS estimate at 3 months of 56%.

Of note, however, was that this trial was conducted across many different clinical sites, some of which had no experience using CAR T cell therapy.

The other abstract that Dr Abrahms highlighted was research on a new target for CAR T cell therapy. To date, much of the success with this investigational approach has been achieved with anti-CD19 CAR T cell therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). However, not all patients respond, and CD19-negative escape has been observed. To overcome this problem and to test an alternative target, researchers at the National Cancer Institute, headed by Nirali N. Shah, MD, developed an anti-CD22 CAR T cell. At the meeting, they will report results from the first few patients treated with this product (abstract 650),  all of whom had CD22+ ALL and had already undergone at least one allogeneic hematopoietic stem cell transplant (HSCT).

In the 4 patients evaluable for response (of 9 treated), the results show a complete marrow remission with negative minimal residual disease. This was achieved in patients who had never received CAR T cell therapy and in patients who had previously been treated with anti-CD19 CAR and were CD19 negative.

"These results are very encouraging...maybe we can make a panel of engineered killer cells that will eliminate leukemia and lymphoma in our patients," Dr Abrahms commented.

Another highlighted abstract also featured a new investigational agent, this time for use in the treatment of myelofibrosis: pacritinib (under development by CTI Biopharma but currently on clinical hold).

Pacritinib is an oral tyrosine kinase inhibitor with activity against Janus associated kinase (JAK) 2 and FMS-like tyrosine kinase 3. The manufacturer hopes that the agent may offer an advantage over currently available agents, through effective treatment of symptoms and less treatment-emergent thrombocytopenia and anemia than has been seen in currently approved and in-development JAK inhibitors.

At the meeting, results from the phase 3 PERSIST-2 study will be presented to show that pacritinib was better than best available therapy (BAT), including the JAK inhibitor ruxolitinib (Jakavi, Novartis), at achieving a sustained spleen volume reduction in patients with myelofibrosis and platelet counts less than 100,000/μL (abstract LBA-5).  The best results with pacritinib were seen with a twice-daily dosing schedule, which was significantly better than BAT in reducing both spleen volume and the total symptom score.

There were some toxiciticies, including hematologic and gastrointestinal, but, importantly, cardiovascular and bleeding events did not differ between pacritinib and BAT, which is why the drug is on hold, Dr Lee commented.

The US Food and Drug Administration (FDA) put a clinical hold  on further development of pacritinib after concerns surfaced about excess deaths and cardiac and hemorrhagic events. In a letter to the company sent in February 2016, the agency noted that the interim overall survival results from PERSIST-2 show a detrimental effect on survival, consistent with the results from the earlier PERSIST-1 study. The deaths in PERSIST-2 in pacritinib-treated patients included intracranial hemorrhage, cardiac failure, and cardiac arrest, the letter noted.

"I think this study is intriguing," Dr Lee said. "Pacritinib did improve symptoms compared to the best available therapy, but it remians to be seen what will happen to this drug when this information is presented to the FDA."

Large Trial of Transplants in Myeloma

Dr Lee also highlighted results from the StaMINA trial, which is the largest trial in the United States to investigate autologous HSCT for multiple myeloma (abstract LBA-1).

The trial involved 750 patients and compared three different approaches. In one arm of the trial, patients underwent a single transplant with the triplet of bortezomib, lenalidomide, and dexamethasone as consolidation therapy, followed by lenalidomide maintenance; in the other two arms of the trial, patients underwent a single or a tandem transplant with chemotherapy consolidation therapy; all received lenalidomide maintenance therapy, which is now standard in the United States, Dr Lee commented.

The results show no difference in PFS or overall survival among the 3 arms, at a median follow-up of 38 months.

Each of the three "seem to be reasonable approaches, with no one approach superior to the others," Dr Lee commented. The inclusion criteria were rather broad, so the results should be generalizable, she added.

New Agent for Sickle Cell Disease

A few months ago, ASH issued  "State of Sickle Cell Disease: A Report," which was a call to action to address gaps in care.

One area is the need for new treatments. "So far there is only one FDA-approved treatment for this disorder (hydroxyurea), even though we have known about the cause of sickle cell disease for more than 50 years," Dr Abrahms commented.

Another drug for sickle cell is on its way: SelG1, an antibody developed by Selexys Pharmaceuticals of Oklahoma, which has been acquired by Novartis. This is a first-in-class humanized antibody against P-selectin, which is an adhesion molecule expressed on activated vascular endothelial cells and platelets. Upregulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interactions involved in the pathogenesis of the acute painful episodes seen in this disease, frequently called sickle cell–related pain crises (SCPC).

Hydroxyurea reduces the frequency of SCPC, but many patients continue to experience acute painful episodes despite such therapy.

New results from the multinational SUSTAIN trial (abstract 1)  show that a new product, SeiGI, can nearly halve the number of pain crises that patients experience during the course of a year (47% reduction seen at the higher dose compared with placebo).

Patients also had a longer time to the first time they experienced a painful crisis, Dr Abrahms noted, and the reduction in painful crises was noted in patients who were already receiving hydroxyurea and in those who were not taking any medication. "So even patients who were on hydroxyurea get an additional bang for their buck," he said.

"I think this is an incredibly exciting study," Dr Abrajhms commented. "When I started in this field, we had nothing to give these patients, other than to support them through their painful crises. Then hydroxyurea came about 15 years ago,  and that reduces pain crises by about a half. Now we have this new product which reduces the painful crises by about half again."

Dr Abrahms also highlighted a presidental session on sickle cell disease, which will be held on the morning of December 6, the last day of the conference. The worldwide impact of this disorder will be described by Kwaku Ohene-Frempong, MD, president of the Sickle Cell Foundation in Ghana and emeritus professor CE of pediatrics, University of Pennsylvania School of Medicine.

Other speakers at the symposium will report on progress being made with three potentially curartive approaches, Dr Abrahms noted, adding to hope that within the next 10 years "we may be able to cure this disease."

Gerd Blobel, MD, from Children's Hospital of Philadelphia, will explain how the remodeling of the chromatin architecture of the β-globin locus can enhance the production of hemoglobin F; Daniel Bauer, from Boston Children's Hospital in Massachusetts, will report on how gene editing can selectively regulate the expression of BCL11A and hemoglobin F; and Giuliana Ferrari, MD, from San Raffaele Institute for Gene Therapy in Milan, Italy, will describe recent advances in gene therapy for sickle cell anemia.

Info Technology and Patient Care

Finally, Dr Lee highlighted a special symposium, to be held  on December 3,  that should be of interest to all practitioners because it will cover the impact that health information technology is having on oncology care. Several speakers will address how electronic medical records have been incorporated into clinical practice, how they can be used for research, and how they could improve patient care.

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