The document summarizes several key studies presented at the 2016 American Society of Hematology (ASH) Annual Meeting. It discusses results from the GALLIUM and ALCANZA studies showing improved outcomes for obinutuzumab and brentuximab vedotin, respectively, in follicular lymphoma and cutaneous T-cell lymphoma. It also summarizes positive results from maintenance rituximab in mantle cell lymphoma and lenalidomide in high-risk chronic lymphocytic leukemia. Finally, it discusses advances in CAR T-cell therapy and results from studies of pacritinib and transplant approaches in myeloma.

1. What's Hot at ASH 2016 Meeting?

2. The GALLIUM study
• 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.

3. 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.

4. The LyMa trial
• 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.
•

5. Practice-Changing Results in CLL

6. The German CLL M1 study
• 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
•

7. Chimeric antigen receptor (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.

8. ZUMA-1 trial
• 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.

9. Anti-CD19 CAR T cell for
relapsed/refractory ALL
• 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.

10. Pacritinib in myelofibrosis
• (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.

11. PERSIST-2 study
• 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.

12. PERSIST-2 study
• 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."

13. 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.

14. StaMINA trial,
• 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

15. SUSTAIN trial :
sickle cell–related pain crises (SCPC).
• 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).

16. SUSTAIN trial :
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).

17. SUSTAIN trial :
sickle cell–related pain crises (SCPC).
• 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."