Category Archives: ASH13

Final ASH13 SnapShot: AbbVie’s ABT-199

Update on ABT-199. 12-3-2013, by @PDRennert 

I reviewed the status of ABT-199 back in August, following ASCO (see link). At the time I felt the drug was being overlooked in the hype around ibrutinib and idelalisib. This was based on impressive response rates and the sense that AbbVie had gotten a handle on how to dose safely. After all, tumor lysis syndrome (TLS) is not uncommon in the treatment of lymphomas, and can be dealt with by dose modification or intervention.

At ASH we get a further look at this drug. Abstract #872, to be presented by J. Seymour, introduces a modified dosing regimen. Patients (rrCLL/SLL, n = 56) were given single doses of ABT-199 at day -3 or day -7, then started on daily dosing after that. This is a Phase 1 monotherapy trial designed to determine MTD. The efficacy readouts were pretty dramatic. ORR = 84% with CR = 21% and PR = 63%. Within the CR group (n = 12), 8 patients had no or very low minimal residual disease. There were 12 discontinuations due to progressive disease (21%). The response rate was not related to del(17p) status but the PR rate was lower in fludarabine-refractory patients (these patients are all at high risk).

Notably, among the usual AEs (diarrhea, neutropenia, URIs, etc) there was an 11% grade 3/4 TLS rate. This is 6 patients. Problematically, TLS was not clearly dose associated: 2 @ 50mg, 1 @ 100mg, 2 @ 200mg and 1 @ 1200mg, this last one resulting in sudden death. So dose optimization remains in progress.

The observation that response was not related to del(17q) status or other aberrations in the TP53 locus in rrCLL patients will be discussed in more detail by M.A. Anderson (Abstract #1304).

M. Davids (Abstract #1789) will present a similar study in a variety of rrNHL patients, including MZL, MCL, DLBCL, FL and WG. Of the 32 patients enrolled and followed for a median time of 6 months, 18 discontinued due to progressive disease (that’s 56%). AEs were typical (nausea, diarrhea, cytopenias, URIs). There were 2 mild episodes of TLS. For FL and DLBCL, doses of 600mg or higher were required for efficacy. The responses were good given this difficult mix of patients. Note that the text and table in this abstract don’t entirely line up, so best to hear the current results at the meeting. The implication here however is that ABT-199 is safer in these patient populations than in rrCLL, a theme we also heard at ASCO.

Aside from the clinical data there is an awful lot of preclinical modeling using cell lines or patient derived cells in vitro or in vivo (mouse). The point of all this nice work is to show the potential of combination therapy using ABT-199 along with other drugs. A few examples:

-  2-DG + ABT-199 kills all Myeloma subtypes (#1921)

-  ibrutinib + ABT-199 is effective against MCL cells and CLL cells (#645 and # 3080)

-  imatinib + ABT-199 kills chronic phase CML cells

-  BTK inhibitor R406 + ABT-199 kills DLBCL cells

   etc, etc

The CML observation points to another trend, which is efficacy of ABT-199 in settings beyond NHL, including ALL (#3919), AML (#885) and MM (#4453). There are others…

On balance this remains an exciting and potentially important drug. The issue of TLS in certain subtypes of NHL remains to be solved, while in other, difficult NHLs there appears to be clear and compelling efficacy with less toxicity.

LINKS TO THE #ASH13 ABSTRACT PREVIEW CHAPTERS @ SUGAR CONE BIO

ASH13 previews

Part 8.   ABT-199
Part 7.   CAR-T tech                        

Part 6b. new targets for Myelofibrosis           

Part 6a. Jak inhibitors in Myelofibrosis                       

Part 5.   Biologics for Non-Hodgkin Lymphomas              

Part 4.   New & noteworthy: CLL etc             

Part 3.   Btk and PI3K inhibitors for CLL      

Part 2.   Ibrutinib                              

Part 1.   Idelalisib

pre-ASH post on ADC technology:  here                         

ASH13 just around the corner – quick update of CAR-T technology

December 2, 2013.
by Paul D Rennert 

Part 7. Chimeric Antigen Receptor T cell technology (CAR-T) in the treatment of hematopoietic malignancies.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
Having detoured briefly into myelofibrosis (see parts 6a and b), there are just a few more subjects to try to cover this week. With luck and time, I’ll get through this bit today and then maybe on to lymphoma genetics, we’ll see.
This is from the introduction to Carl June’s seminal 2011 NEJM case report:
“We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 … (4-1BB) and CD3-zeta … signaling domains. A low dose (approximately 1.5×10^5 cells per kilogram of body weight) of autologous chimeric antigen receptor–modified T cells reinfused into a patient with refractory … CLL expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia.” (Porter et al. 2011. NEJM 365: 725-733). The therapy induced long term remission is a patient who had failed 4 rounds of rituximab+chemo, and then had failed alemtuzumab, anti-CD52, therapy. Pretty amazing.
The anti-CD19 CAR is essentially an antibody fragment containing a single chain Fv (antigen binding domain). The CD3-zeta chain induces T cell activation and the addition of the 4-1BB cytoplasmic domain ensures prolonged and robust response – 4-1BB is in immune checkpoint activator, and is gaining some favor in its own right in immunotherapy, through the development of agonist anti-4-1BB antibodies. The CAR-T components are introduced to the patient’s own T cells ex vivo via lentivirus transduction, then given back to the patient in hopes of inducing a T cell mediated immune response to the cancer (e.g. a CD19+ CLL). The original case reports were followed for up to 3 years, as reported in Abstract #4162. Of 14 patients treated in the pilot studies, the ORR = 57% (21% CR and 30% PR). 43% of patients did not respond. Of the PR cohort, 40% progressed within 4 months. So that’s about 1/3 of patients with a durable response.
Additional clinical trials have been funded via collaboration with Novartis, who has bought the technology and patents. A few of these are updated at ASH. The CLL and ALL data for patients treated with the anti-CD19 CAR T cells (CTL019) are summarized in Abstract #163. 24 rrCLL patients have been treated using 2 different protocols that vary by the number of CTL019 cells given back to the patient. The response rates were CR = 21%, PR = 29% (so ORR = 50%) and non-responders = 50%. In pediatric ALL (n=14) the CR = 57%; the rest of the patients (43%) either did not respond or progressed. In adult ALL, all 3 patients had a CR (=100%). CRs were always accompanied by in vivo expansion and persistence of CTL019 cells. Tumor cells were eliminated from circulation and also, importantly, from bone marrow. Molecular analyses showed that tumor cells were essentially eliminated in patients with CR – this is defined as minimal residual disease (i.e. not detectable). Additional data specific to these studies are reported in Abstract #873 (CLL) and Abstract #67 (ALL) – the latter study reports persistence up to 15 months. Another group at U Penn reported similarly high RRs in ALL. Lee et al (Abstract #68) report the use of an CD19-CD28-CD3zeta CAR construct to engineer t cells for use in ALL, with an initial CR (n=7) of 71.5%, with other 2 PR responders and 2 non-responders. These are impressive early data from multiple studies.
Steve Rosenberg’s group is also reporting use of anti-CD19 CAR-T cells, these made using a gamma-retrovirus construct to genetically modify the T cells. The technology differs also by use of the CD28 signaling domain instead of 4-1BB, along with CD3-zeta. Of 14 patients with rrCLL, rrDLBCL or primary mediastinal BCL, 36% achieved a CR and 43% a PR, the rest being non-responders or SD. All responders (PR + CR = 79%) were ongoing at the time of abstract submission. The study will be further updated at the meeting. The trial was funded under a CRADA-based collaboration between the NCI and Kite Pharma, a private biotech company.
Given the compelling response rates observed, it is unclear whether the ex vivo selection and expansion methods employed by the MD Anderson group will add benefit. Laurence Cooper and colleagues will present a CD19 CAR technique that utilizes artificial antigen-presenting cells to select the T cell population that is then given following hematopoietic stem cell transplantation in ALL and NHL patients (Abstracts #166 and #4208). Their very early results will be updated at the meeting. Additional efforts targeting CD19 include the trial in rrCLL patients who have received only 1 prior chemotherapy regimen; the idea is that these patients are earlier in the disease course and may have better response rates. It is not possible to tell from the Abstract (#874) if this effort is succeeding, but an update is promised at the meeting.
Turning from the CD19-directed technologies, Carl June’s group is presenting the first clinical data on the use of engineered T cells in multiple myeloma. The T cells are expanded using CD3/CD28 beads (a technology I worked on 20 years ago at Repligen, in the context of HIV therapy) and are engineered to express a modified TCR that recognizes the MM antigens NY-ESO-1/LAGE1. The recognition of this peptide complex is HLA-class restricted, so the patients are screened in advance for responsive HLA haplotypes. The T cells are infused followed depletion and stem cell transplantation, so CAR-T is used here in the context of adjunct therapy. Best response ORR = 100%, although some patients have since progressed. An update will be given at the meeting. Also of note is a trial in which this novel CAR-T therapy is used in a non-transplant setting (no data available yet). An interesting twist is the use of kappa-light chain of surface immunoglobulin expressed on malignant B cells (as opposed to lambda light chain expressed by most normal B cells? – I guess that’s right). A group from Baylor, funded by Celgene, will present Phase 1 data (Abstract #506). Another CAR antigen technology in preclinical development at U Penn targets CD123 for AML (Abstract #143). Preclinical data from the OSU group show that a different MM antigen can be used in the CAR-T setting. Abstract #14 shows that a CS-1 directed CAR works in a mouse xenograft model. I like the straightforward description of the technology: “We successfully generated a specific CS1-CAR construct with a lentiviral vector backbone, sequentially containing a signal peptide (SP), a heavy chain variable region (VH), a linker, a light chain variable region (VL), a hinge, CD28 and CD3epsilon.” Simple, right? Finally, Haso et al from the NIH compare CD22-targeting CAR constructs using different signaling chains (4-1BB v CD28) in preclinical mouse models of ALL, and report superior results using the 4-1BB construct (Abstract #1431). This is nice as they used a humanized mouse model, the NOD/SCID/Common gamma chain KO mouse (NSG), engrafted with a human ALL line. Love the humanized mouse technology, right up my alley.

A persistent theme in the evolving treatment of leukemias and lymphomas is the use of combination therapies. We see a similar trend developing with CAR-T technologies. Paolo Ghia et al combine a CAR directed to CD23 along with low dose lenalidomide treatment using the Rag2/Common gamma chain KO humanized mouse model and cell from CLL patients – nice work (Abstract #4171). A second study evaluated the use of mTOR modulation in the context of CAR-T therapy (Abstract #4488). As this technology continues to advance we can expect to see additional uses of targeted or other therapies in combination.

ASH 2013 preview: Myeloproliferative Neoplasms, New Targets

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)
Part 6b. Myelofibrosis and related Myeloproliferative Neoplasms: Phase 1 and preclinical updates from ASH 2013.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
 
Back to it. In part 6a we looked at the phase 2/3 studies, and these are certainly focused on Jak inhibition, for reasons we discussed in part. Its worth noting that Jaks are a class of signaling proteins that hybridize shamelessly and because of this blocking any given Jak (Jak1, Jak2, Jak3, Tyk2) will necessarily block the activity of others in the context of signaling that requires hybridization. Conversely it has been demonstrated that blocking any given Jak may not be effective in settings where other family members can substitute. As always, it is complicated.
 
It has been mentioned that Jak inhibitors are not considered disease modifying or curative. They offer symptomatic relief, which relieve the pathological degradation of the bone marrow, and can do so for extended periods, as has been demonstrated with ruxolitinib. In this sense the treatment paradigm is not so different from some other targeted cancer therapies, where the name of the game is to keep the wolf from the door, at least for a time.
 
Regardless of the limited potential, Jak inhibitor development continues at a brisk pace, as demonstrated in the previous section. In earlier development we find yet more Jak inhibitors. Gilead will present data from the phase 1/2 trial (with extension) of the Jak1/2-selective inhibitor, momelotinib (Abstract #108). Confusingly, this trial used some new (to me) endpoints. One was a reduction in “palpable splenomegaly” which suggests the spleen was not imaged (?). Second (and useful I think) was “transfusion independence”. I like this because it clinically measures the impact of treatment on the most pathologically relevant endpoint, loss of RBCs and platelets in circulation. What is even more interesting about this trial is the extension data, showing a “median spleen response” of 324 days, with pretty huge variance. As noted with ruxolitinib, the variance cannot be traced to the presence or absence of Jak2 V617F mutation - I suspect Gilead will work to sort this out pretty quickly, so that bears watching unless of course the variance is due to the manner of measurement!
 
Early trial data will be reported for BMS911543, another Jak2-selective inhibitor (Abstract #664). Note that Jak3 and Tyk2 are hit with IC50s less than 100nM, so selectivity will depend on actual exposure, which is data not available yet. Anyway, the drug is given BID and the goal of the trial is to establish an MTD (not reached). Early efficacy data included analysis of responses of patients who had received a prior Jak inhibitor. Symptoms were well controlled and the spleen volume response (> 35% reduction in splenomegaly) was dose responsive – up to 70% of patients responded at the highest doses (note: small sample size). AEs were were the usual diarrhea, nausea and cytopenias. The investigators will update with data from 84 patients at the meeting.
 
Eli Lilly will present data from the LY2784544 phase 1 dose escalation trial (Abstract #665). Of note, this drug is described as being “selective” for the V617F mutant of Jak2. They are enrolling 38 patients (most MF, some PV) at 30 -300 mg per day, although at 200 mg and above they hit liver tox (grade 3 serum creatinine elevation) and the MTD is established at 120 mg/day. Other AEs are typical of the class and not severe. We are introduced to yet another way of measuring splenomegaly, this time as “spleen length”. There was a >50% improvement in 56% of the evaluable patients, furthermore, >50% of patients reported improved symptoms by TSS. An update is promised for the meeting.
 
Novel inhibitors are finally moving through preclincal and early clinical evaluation. Geron has a novel telomorase inhibitor, imetelstat, a lipid-conjugated oligonucleotide inhibitor of human telomerase (Abstract #662). Early data are impressive. AEs were modest, and responses (44%) included a fair number that appeared to be CRs or PRs. Here I quote: 
 
“The four (22%) CR patients experienced reversal of BM fibrosis and recovery of normal megakaryocyte morphology. Two CR patients were transfusion-dependent at baseline and became transfusion-independent … Among 13 patients with leukocytosis, 10 (77%) normalized their count or had >50% reduction. Eleven (61%) patients had complete or partial resolution of leukoerythroblastosis.”
 
Thats pretty impressive. The downside is that this was a small single center open label trial, so really, we just have to wait and see.
 
For an example of why such results can be so misleading, let look at a Phase 3 trial failure (Abstract #394). Here we have Celgene’s pomalidomide (approved under the name Pomalyst for the treatment of Multiple Myeloma). Phase 2 trials suggested that pomalidomide imporved severe anemia in MPN patients, including MF, PV and ET patients. The phase 3 trial enrolled 252 patients with MPN-associated MF who were dependent on RBC transfusions. There was no significant improvement in time to transfusion in drug-treated v placebo-treated cohorts.
 
So these early trials can be very misleading, but lets look even earlier, at some preclinical studies.
 
Novartis has some nice data showing elevation of Hedgehog signaling pathway targets in MF granulocytes (Abstract #666). Using in vitro and in vivo (mouse) models they demonstrate that Jak inhibition and Hedgehog inhibition have additive activity. The Jak inhibitor was INC424 and the Hedgehog inhibition was provided by Smoothened antagonism (sonidegib). Another novel approach is to target megakaryocytes, that contribute to MF pathogenesis. Using in vitro and in vivo models an academic collaboration (Abstract #109) shows that Aurora A kinase inhibition induces megakaryocyte arrest and this results in decreased bone marrow fibrosis, decreased infiltration of megakaryocytes and granulocytes into the liver and spleen, and decreased plasma TGFbeta, a potent pro-fibrotic growth factor.
Genetic analyses have demonstrated that certain signatures indicate risk for increased risk of leukemic conversion and decreased OS. These include ASXL1, EZH2, IDH1/2 and SRSF2 gene mutations (Abstract #104). EZH2 mutation accelerates the onset of primary MF (Abstract #110). However, patients carrying these mutations are not differentially impacted by ruxolitinib therapy, instead they have similar responses to patients without such mutations (Abstract #105). Novel pathways associated with MF include the arachidonate 5-lipoxygenase pathway (Abstract #111). An exciting new development is the identification of calreticulin mutations in patients that do not have Jak2 mutations, that is, the two appear to be mutually exclusive (Abtract #LBA1). This will spur investigation in novel drivers of MPN pathogenesis.
Obviously there is much more going on then can be covered here. The identification of the Jak2 mutation in MPN opened up a new era of drug development for these rare but nasty and lethal neoplasms. New findings will push us even further, and we can reasonably expect to see important advances over the next few years.
 
 

ASH13 SnapShots, part 6, Myelofibrosis: How Many Jak Inhibitors Are There?

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)

Part 6a. Myelofibrosis: Therapeutic agents in Phase 2/3.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

I’m splitting this into 2 parts because, well, lets just say there is always a lot to learn. Myelofibrosis is a proliferative cancer of myeloid lineage cells, characterized by bone marrow infiltration and fibrosis, splenomegaly and heptomegaly caused by extramedullary hematopoiesis, and overall disruption of hematopoiesis leading to cytopenic conditions such as anemia and thrombocytopenia. Patients experience diverse symptoms, which has led to the development of patient symptom scoring systems. They are at risk for transformation to acute myeloid leukemia, and in general have greatly reduced overall survival due to chronic anemia leading to bone marrow failure.

Myelofibrosis (MF) is one of a class of myeloproliferative neoplasms (MPN) that also includes Polycythemia Vera (PV) and Essential Thrombocytopenia (ET). In 2005 it was found that nearly all PV cases and about half of MF and ET cases had a mutation in Jak2 (V617F). This marked the beginning of novel drug development for MPN that culminated with the 2011 approval of ruxolitinib (Jakafi) for the treatment of intermediate risk (intermediate-2) or high risk MF. Ruxolitinib is a Jak1/Jak2-selective inhibitor.

The clinical landscape for MF remains dominated by Jak inhibitors, and to go through them is an exercise in duration. Lets spare you all that, and try to summarize quickly, hitting high and low points when they appear. At the outset its fair to make a few generalizations. First, Jak inhibitors are not curative and do not induce PRs or CRs in the way we have discussed in earlier sections. Second, Jak inhibitors themselves can cause cytopenias, and they are therefore dose or duration limited. So, this becomes a balancing act between efficacy (by inhibition of myeloid-lineage cell proliferation) and toxicity (due to inhibition of hematopoiesis). 

Lets sort these by clinical stage.

Sanofi is presenting results from a phase 3 trial of fedratinib, a Jak2-selective inhibitor (Abstract #393). In this trial of patients with high risk or primary (i.e. active) MF the primary endpoints are splenomegaly and patient reported symptoms. Patients have to present with platelet counts above 50 x 10^9/L. 67% of the patients were positive for the V617F Jak2 mutation. 40% of evaluable patients reached the spleen response rate of > 35% reduction in spleen volume as measured by MRI or CT. About the same percent recorded improvement in platelet counts and about 30% of patients reported improved symptoms. This is very much like the ruxolitinib results, as are the AEs reported, which include diarrhea, anemia, higher risk for infection, among others.

UPDATE: via FierceBiotech “A few days ago the pharma giant had to shutter a program for fedratinib after the FDA ordered a clinical halt when their myelofibrosis patients developed Wernicke’s encephalopathy–a neurological condition spurred by biochemical brain lesions.”

Well, thats the end of that drug (another abstract below, just to be thorough). This tox issue is clearly not a class effect, that is, not a Jak inhibitor issue. Instead this drug either hits another signaling or other protein target (that might be interesting). Alternatively, and perhaps more likely, this is compound specific toxicity. Either way, the fact that this tox issue was missed until now (phase 3) is remarkable.

Sanofi also has results (Abstract #661) from a phase 2 trial of fedratinib in MPN patients who were previously on ruxolitinib (so these are ruxolitinib resistant or intolerant). These patients presented with splenomegaly, as evidence of disease activity, and had to have platelet counts above 50 x 10^9/L. The presentation is of results obtained at the 12 week interim cutoff point. Somewhat remarkably (to me anyway) the spleen response rate (defined above) was about 40%. The patient reported outcome was modest, but measurable. This suggests that moving from one Jak inhibitor to another is not as silly as it might sound (we’ve seen this before: anti-TNFs in RA; IFN betas in MS). The downside was the toxicity: 26% of patients discontinued due to AEs that included some grade 3/4 (severe) diarrhea, and a very high rate of anemia and thrombocytopenia. It will be important to track patient outcomes and AEs going forward in this trial.

Incyte will report on a Jak1-selective inhibitor INCB039110 that is in an open-label MF Phase 2 trial (Abstract #663). The primary endpoint in this trial is patient reported symptom score (TSS). Inclusion/exclusion criteria were similar to what is described above. While there was a dose dependent improvement in TSS, there was only a modest improvement in the more objective endpoint of change in spleen volume. Importantly however, Hb level (a measure of RBC count) and platelet counts were preserved. This suggests that Jak1 inhibition might be useful, assuming that there is reasonable efficacy.

Just to remind us how confusing this all can be, Cell Therapeutics will present results obtained in a Phase 2 trial of its Jak2.Flt3 dual inhibitor, pacritinib (Abstract # 395). This trial enrolled patients with primary or secondary MF and included patients whose platelet counts were below 100,000/microliter. This low number is prognostic for transformation to a leukemic state and further, patients with such low counts were specifically excluded from the ruxolitinib registration trials (COMFORT III). 82% of patients had the Jak2 V617F mutation. So, Cell Therapeutics is trying to differentiate pacritinib here, and they are successful. Approximately 40% of patients achieved > 35% reduction in spleen volume. Most patients maintained stable platelet numbers if Hb levels. Notable also were the modest AEs reported. This is an interesting therapeutic to watch.

Next we’ll look at some earlier therapeutics, including novel (i.e. non-Jak targeting) therapies, coming up in part 6b.

SnapShots from the 2013 American Society of Hematology Abstracts – Part 5

 
Part 5. Key Biologics in Clinical Trials.
November 20, 2013
The American Society of Hematology Meeting will take place in New Orleans,
December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
In parts 1-4 we meandered through the small molecule, mainly oral drugs,
highlighting a few key pathways and focusing mainly on CLL.
Biologic drugs are a different and equally important class of therapeutics for lymphoma
treatment, and really it is Rituxan, the antibody that depletes cells expressing CD20, that
ushered in the new era of non-chemotherapy-based drugs. Some of the small molecule
trials discussed earlier were done in combination with anti-CD20 antibodies with or
without added chemotherapy. This therapeutic trend toward combination therapy will
dominate the lymphoma landscape, with chemo, targeted small molecules, and antibodies available to mix and match, just so long as they are not too toxic when combined, provide additive efficacy, and we can afford to pay for them. One might also overlay immuno-
therapy approaches – checkpoint modifiers, CAR-T modified cells, even cancer vaccines -
and of course there is also the whole bone marrow or stem cell transplantation field.
There are notable new biologics being developed for the treatment of lymphoma, and a
few of these have new data available in the ASH 2013 abstracts.
The real question is whether anything will be able to compete with the novel anti-CD20
mAb obinutuzumab.
Obinutuzumab (GA101) is aglycoengineered antibody having 10-fold greater affinity 
for FcgammaR3A. This is receptor on cytotoxic NK cells that binds to the Fc domain 
of the antibody. The binding of the Fc domain to the FcR (receptor) triggers killing of 
the target (CD20+) cell by the interacting NK cell. Obinutuzumab was approved under 
the brand name Gazyva on November 1st for use in combination with chlorambucil to 
treat patients with previously untreated CLL. This was this first drug approved under 
the FDA’s new breakthrough therapy designation and wasbased on a Phase 3 study of 
previously untreated CLL patients (n = 365) comparing Obinutuzumab plus chlorambucil 
to chlorambucil alone. The PFS for the combination therapy was 23 months compared 
with 11.1 months with chlorambucil treatment. Additional data from the Phase 3 trials, 
comparing obinutuzumab pluschlorambucil (OB-c) to rituximab (Rituxan) plus 
chlorambucil (R-c), are to be presented during the plenary session at ASH (Abstract #6). 
Those data are summarized as follows:
ORR
CR
MRD*
PFS
OB-c
78%
21%
29.4%
26.7 months
R-c
65%
7%
2.5%
15.2 months
*: MRD is minimal residual disease, meaning that bone marrow and organs are negative 
for tumor cells.
AEs were higher in the obinutuzumab plus chlorambucil arm, although it appears that 
this was due to increased severe infusion-related reactions, which can be controlled.
Another study in previously untreated CLL patients will be presented at ASH (Abstract
#523). In this trial, obinutuzumab (OB) was combined with fludarabine/cyclophosphamide 
(FC) or bendamustine (B). There are 41 patients enrolled and the median reported followup 
time is nearly 12 months. 9 patients (22%) had to discontinue treatment due to AEs, mainly cytopenias. The investigators will report and update response data, summarized here (note 
that CRi, defined as complete response with incomplete bone marrow resolution, is included 
in this table with the %PR):
ORR
CR
PR
SD
PFS
OB-FC
62%
9.5%
47.6%
19%
not reached
OB-B
90%
20%
70%
0
not reached
No responding patients progressed and PFS was not reached. While the data look very good
for efficacy, the fact that a high percentage of patients had to discontinue due to AEs is
notable.
Two other studies will be presented at ASH. One is on the treatment of CD20+ Diffuse
Large B Cell Lymphoma (DLBCL) patients in a Phase 2 clinical trial (Abstract #1820).
DLBCL is an aggressive lymphoma, currently treated with combination chemotherapy
(CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone) or with rituximab plus combination chemotherapy (R-CHOP). In this trial, 80 previously untreated DLBCL
patients were treated with obinutuzumab plus CHOP. The ORR = 83%, consisting of
CR = 55% and PR = 28%. Of the 80 patients total, 11 patients discontinued treatment,
5 of these due to AEs (6.25%), but in general AEs were manageable. Nine patients had
PD, three died. These preliminary results are very encouraging, updated results including
analyses responses in DLBCL subsets (ABC v GC) and with reference to molecular
classification will be presented at the meeting. An earlier study (Abstract #1814) will
present data on the use of obinutuzumab as maintenance therapy after induction therapy
with chemo (either OB-CHOP or OB-FC). Patients had rrFL (follicular lymphoma). The
induction data was published by Radford et al. in Blood, 2013, volume 122, page 1137ff. 
CR rate was monitored at the start and end of maintenance therapy, with the maintenance 
period being a median of 35 months across the two cohorts. CR as a best overall response increased on maintenance with obinutuzumab in the OB-CHOP cohort (52%, PFS not 
reached) and in the OB-FC cohort (82%, median PFS = 46 months). Finally, a combination 
trial of obinutuzumab and ABT-199 is currently in phase Ib (NCT01685892).
These studies show benefit of obinutuzumab therapy in different lymphoma populations
using a variety of treatment paradigms, and point to the importance of this biologic
therapy in B cell lymphoma treatment.
There are a large number of new biologics competing for attention; just a few are discussed
here.
Another anti-CD20 antibody with breakthrough status is ofatumumab (Arezza). Approved in
2009 for use in rrCLL patients, this antibody is moving toward use earlier (i.e. in newly
diagnosed CLL) and in other patient subsets.
In May of this year, positive phase 3 data for ofatumumab were announced by GSK. Patients
with previously untreated CLL (n = 447) received ofatumumab plus chlorambucil (OF-C) or chlorambucil (C) alone. The study found that patients in the ofatumumab cohort experienced
a longer median PFS. That study will be updated at ASH (Abstract #528). Top line data is
here:
PFS
ORR
CR
MRD
OF-C
22 months
82%
12%
4%
C
13 months
69%
1%
0
Other studies on ofatumumab being presented at ASH include a phase 2 trial in combination
with dexamethasone, to treat high risk rrCLL patients (Abstract #2877). This study presents
a CR = 16% and PFS = 10 months, although the infection risk was quite high. Another
phase 2 study is testing the efficacy of ofatumumab in combination with the AKT inhibitor afuresertib (Abstract # 4175) in the treatment of high-risk rrCLL patients. In this small
study (n = 19) AEs were manageable (neutropenia, GI complications) but responses were
low: ORR = 42%, CR = 0, PR = 42%; 58% of patients had SD, and 26% of patients
progressed. Several other trials will also be updated (Abstracts #1645 and 4177).
An example of the high bar set by obinutuzumab therapy can be seen in several trials of
other biologics. Pfizer has developed an antibody/drug conjugate (ADC) called inotuzumab ozogamicin (InO). This is a humanized anti-CD22 antibody conjugated with calicheamicin, 
a potent cytotoxic. CD22 is expressed on most forms of NHL. The trial (Abstract #1821) 
is a phase 1 dose escalation trial designed to identify the MTD in combination with 
rituximab plus chemo (gemcitabine, dexamethasone, and cisplatin). AEs, mostly
cytopenias, causing dose reductions and dose delays established the MTD. Patients had 
rrNHL, with 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL.
At the MTD dose the ORR = 45% and the CR = 22%. Of the 55 patients enrolled, 12
(22%) discontinued due to AEs and 12 (22%) discontinued due to PD. These numbers
are a little worrisome although this is a difficult patient population to treat. It will be
important to see PFS and OS numbers as clinical development of this therapy continues.
An intriguing target for antibody development is CD37. CD37 is tetraspan protein expressed
on a variety of hematopoietic cells, and can transmit a cell death signal through its SHP-1
domain. Trubion engineered a modified antibody called TRU-016, now being developed by Emergent (see the 14 November issue of Blood – volume 122, p 3397 – for a brief description 
of this and other anti-CD37 targeting agents). Phase 2 data on TRU-016, now called 
otlertuzumab, will be presented at ASH. Otlertuzumab induces cell death directly (ie. by 
signaling cell death) and also through Fc-mediated cytotoxicity. The phase 2 trial recruited 
65 rrCLL patients who had failed between 1 and 3 prior therapies. The Abstract (#2860) 
presents data on 44 evaluable patients treated with otlertuzumab (OTL) or with otlertuzumab
plus bendamustine (OTL-b). The data are as follows:
treatment
ORR
CR
% progression
OTL
42%
4%
46
OTL-b
80%
20%
10
The % progression data refers to the responding patients only. AEs were in line with the chemotherapy treatment. A second study (Abstract #4165) provides preliminary data on
patients treated with otlertuzumab plus the anti-CD20 antibody rituximab (Rituxan). This
dual antibody therapy was given to previously untreated CLL patients. Preliminary data
suggest an ORR = 88%, and modest AEs. This trial will be updated at the meeting. These
early studies suggest that targeting CD37 is an attractive approach for CLL therapy.
BITE antibodies are bi-specific antibodies originally developed by Micromet. They have
received a lot of press following the 1.2 billion dollar acquisition of Micromet by Amgen. Blinatumomab binds to CD3 on T cells and CD19 on lymphoma cells, helping to direct the
T cells to recognize and destroy the tumor cell (BITE stands for BI-specific T cell Engager). Abstract #1811 has some very early data on blinatumomab treatment of rrDLBCL patients.
Lets be clear upfront that this is a tough patient group to treat. At the time of abstract
submission, 11 patients were enrolled with initial ORR = 57%. It will be very interesting
to hear updated results from this trial at ASH, including both efficacy and AEs, which at
first glance seem tolerable if unpleasant (including CNS toxicity).
MEDI-551 is an afucosyl-anti-CD19 antibody with augmented cytotoxic activity (due to the
lack of fucosylation of the antibody). An 83 patient Phase 1 trial (Abstract #1810) enrolled heavily pretreated rr CLL, DLBCL, FL, or MM (multiple myeloma). All of these B cell lymphoma types are CD19 positive. The ORR = 25%, with CR = 10.8% and PR = 14.5%.
50.1% of patients were characterized as SD. PFS was calculated to be 9 months. At first
glance the single agent responses are substandard; MedImmune is continuing development
of MEDI-551 in combination with chemotherapy.
A CD19 ADC has advanced to phase 2, in a combination trial with rituximab (Rituxan).
SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a cytotoxic
agent. It is under development by Sanofi and was licensed from ImmunoGen. This ADC
was given along with rituximab (Rituxan) to rrDLBLC patients (refractory to first line
therapy or relapsed after a prior therapy; Abstract #4395). ORR was low at 31% and 36%
of responders progressed by the end of the study. Sanofi plans to move this agent into
patient populations that may be more responsive.
So, here we have seen two anti-CD19 antibody therapeutics with rather poor efficacy
profiles.
I want to end with an old dog/new trick story concerning alemtuzumab. First studied many
years ago in the context of transplant rejection therapy, this anti-CD52 antibody lives on as
a treatment for hematological malignancies (CD52 is widely expressed) and, under the
brand name Lemtrada, as a therapy for multiple sclerosis. The long strange trip of this
nasty antibody (the side effect profile is not good) is the subject for another day. Of interest
at ASH however is a nice study looking at the utility of alemtuzumab for very high risk
treatment naive CLL patients (Abstract #2861). High risk is defined here genetically – these
are patients with genetic deletions or mutations known to be associated with poor prognosis. Without diving into the details, the investigators have shown that TP53 mutations had an
adverse prognostic impact and shorter PFS and this was overcome by alemtuzumab treatment. This then presents itself as a potential therapeutic for patients known to have this poor risk
factor.
If time allows I want to discuss the CAR-T technology, perhaps in the next section.

SnapShots from the 2013 American Society of Hematology Abstracts – PART 2

Part 2. Small molecule BTK inhibitor Ibrutinib in the treatment of Chronic Lymphocytic Leukemia (CLL).
November 15, 2013
The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
Note that I’ve defined most of the terms we are using in Part 1, so please refer to that section for help with any abbreviations. In Part 1 is also some background on CLL and the signaling pathways downstream of the B Cell Receptor, which are targeted by these drugs. Finally, I introduced the patient populations typically encountered in CLL clinical trials.
So now we come to the Btk inhibitors and specifically to Ibrutinib, the Pharmacylics compound partnered with the Janssen arm of Johnson & Johnson. This soon-to-be blockbuster drug has been approved for the treatment of Mantle Cell Lymphoma (MCL) at an anticipated cost of 150,000 USD/year.
As mentioned in Part 1, CLL is the most common of the B cell lymphomas, so it is of keen interest to see how Ibrutinib performs in that patient population, especially given the efficacy seen with Idelalisib from Gilead.
Abstract #675 presents data from a 40 patient phase 2 trial in which Ibrutinib (IBRU, 420mg/day) was given with Rituxan anti-CD20 antibody (Rtx). The trial is notable for the inclusion criteria that enrolled patients only if they had high-risk disease: del(17p) or TP53 mutation (treated or untreated), PFS < 36 months after frontline chemotherapy + anti-CD20 treatment, or relapsed CLL with del(11q). Most patients responded well (see the table), very few patients were lost to followup and AEs were well tolerated.
Abstract #525 presents data from a small phase 1b trial in high-risk rrCLL/SLL patients (SLL is a form of CLL called small lymphocytic lymphoma, in which most of the cancer cells are located in lymph nodes). In this trial patients received IBRU + Rtx + B (bendamustine, see part 1). The response rate was very high (see the table) although the authors do note that 30% of patients eventually discontinued treatment, 10% due to progressive disease. Responses appeared to be independent of specific high-risk cytogenetic factors. Grade 3 or higher AEs were GI related, cytopenias (including 6.7% febrile neutropenia), and infections. The data from these 2 abstracts are shown below, and compared to published data (Byrd et al. 2013 NEJM 369:32-42). Note the caveats described above when reading these response percentages.
 
 
It is a little hard to directly compare these results with the Idelalisib data, partially reproduced here from Part 1, with one correction to the table (column 3: DOT = median duration of treatment):
 
 
It is tempting to conclude that the response rates with Ibrutinib are a little higher, but such comparisons will required much larger data sets. At the moment it is fair to say that these therapeutics both provide superb novel options for rrCLL patients.
Returning to Ibrutinib, there will be additional data from monotherapy studies shown at ASH. Abstract #4163 reports on an extension study of Ibrutinib monotherapy in treatment-naive CLL and in rrCLL patients. An important parameter of this study is that it included treatment-naive (likely newly diagnosed) patients; the data for discontinuation due to disease progression (PD) shows that nearly all of these early-treated patients maintain a response for at least the DOT.
After 2.5 years, 76% of this patient population was still alive, an impressive number.
Abstract #673 also examined the impact of Ibrutinib monotherapy, in this case in elderly patients with or without the del(17p) cytogenetic factor indicating high risk for progression. In this study there was a significant difference in the PR percentage, with 81% of patients with wild-type 17p responding while only 53% of patients with a deletion of 17p responded (p = 0.04). This suggests more (or larger) studies will be required to sort out the best patients for Ibrutinib therapy.
A very nice study will be presented by investigators at The Ohio State University (Abstract # 2872). Using multivariate analyses of patient response, progression and survival, these investigators compare Ibrutinib monotherapy to checkpoint-inhibitor therapy (alvocidib, dinaciclib, or TG02) to “other” therapy, in del(17p) rrCLL patients. “Other” is unfortunately not identified, but must include standard-of-care, which would normally be chemotherapy plus Rituxan. Here is a snapshot of the data at 24 months (the analysis is beautiful and I won’t reproduce their graphs here):
These data really drive home the importance of the new therapeutics and new therapeutic combinations, where we are seeing improvement in PFS.
There are a swarm of newer small molecule drugs coming up, and these will be covered in Part 3.

SnapShots from the American Society of Hematology Abstracts, Part 1

November 15, 2013
The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
Part 1. Small molecule PI3Kdelta inhibitor Idelalisib in the treatment of Chronic Lymphocytic Leukemia (CLL).
It is useful to remember that most CLL patients have indolent disease and are in a “watch and wait” mode with their physicians, who will not initiate treatment unless they see signs that the cancer is becoming active and/or the patient has one or more risk factors. Therefore in clinical trials the CLL patients are those at high risk. Typically “relapsed or refractory” CLL (rrCLL) patients have cytogenetic markers of poor prognosis (mutated p53, del(17p), del(11q), trisomy 12, mutated NOTCH1), or are patients who have failed multiple prior therapies (chemotherapy and/or antibody therapy such as Rituximab treatment), patients with “bulky” disease indicating lymph node and other lymphoid organ involvement, and patients with unmutated IGVH sequences. Often these high risk markers occur together. It is important to realize that at this time CLL is not considered a curable disease, and that the goal is therefore to increase median progression-free survival (PFS) and median overall survival (OS), the latter referring to time until death.
That said, we are witnessing a remarkable time. Terrific new therapies are being developed, and physicians look forward to offering their patients a chance at a cure.
Lets start with a drug class I think has great promise, inhibitors that act downstream of B cell receptor (BCR) signaling. CLL is a B cell lymphoma, and is dependent on chronic activation of these signaling pathways. Here is a model to get us oriented, from the Onclive website:
Note that Syk, Btk and PI3K are upstream (relative to the cell surface and BCR) and therefore are critical components of the pathway. Drugs targeting each of these signaling kinases have been developed. AKT, mTOR and others, generally more familiar to us from the solid tumor literature, are further downstream.
There are four isoforms of PI3K relevant to the drug class: alpha, beta, delta and gamma. Different drugs have selectivity for one or more of the isoforms.
For treatment of CLL, the lead therapeutic in the class Idelalisib is a PI3Kdelta(d) selective inhibitor from Gilead. PI3Kd signaling is known to be essential for the activation, proliferation, survival and tissue homing activity of lymphoma cells. On October 9th a phase 3 CLL clinical trial of this drug was stopped ahead of schedule based on a positive risk/benefit assessment. The drug is also under New Drug Application (NDA) review for indolent Non-Hodgkin’s Lymphoma iNHL) based on results from multiple phase 3 trials. Idelalisib is trailing just a step behind Ibrutinib, a BTK inhibitor, in the approval process – Ibrutinib was approved for Mantle Cell Lymphoma (MCL) on November 12th. Neither drug is approved for CLL, the most common lymphoma.
Both drugs have moved aggressively into combination therapy trials. Some of the early trials (phase 1 and 2) will report out interim data at ASH.
Abstract #4176 presents analyses of Idelalisib (IDELA) given in combination with Rituximab (Rtx) antibody therapy plus chemotherapy (B: bendamustine or C: chlorambucil) in high-risk rrCLL patients. Results are encouraging and shown in Table 1, where ORR = stable disease (SD) + partial response (PR) + complete response (CR). Its important to note that these are clinical trial terms and do not reflect outcomes, just observations at specific timepoints. Regardless we are looking for high % ORR, PR and CR. Importantly, the median duration of exposure was 18 months at the time of analysis, meaning that 18 months is the median amount of time patients have been exposed to drug without withdrawing due to toxicity, disease progression, or death. More importantly, the median duration of response (DOR) to therapy had not been reached within the 18 months (so that’s good, patients are still on drug and are still responding) nor had the median PFS been reached (so more patients have survived than have not survived). The IDELA-Rtx-C data are similar, just of shorter average duration with a median exposure = 7.7 months (I’m guessing here that this arm of the trial enrolled later). Also notable is the toxicity data from this trial, which tracked pretty consistently with the chemotherapy regimen. When the combination therapy included bendamustine, neutropenia was the defining toxicity, with > 60% of patients experiencing grade 3-4 neutropenia. When the combination therapy included chlorambucil, liver transaminase elevation was the defining toxicity, with > 21% of patients experiencing grade 3-4 liver toxicity. Its important to realize that these are severe, but manageable, toxicities for most patients.
Abstract 2878 presents a similar study, but in this case the combination therapy given with Idelalisib was limited to chemotherapy. Chemotherapy consisted of B: bendamustine, F: fludarabine or C: chlorambucil, given in standard doses. This trial was run in a heavily pre-treated patient population having a very poor prognosis. The data are very encouraging given the composition of the enrolled patient population (Table 1). The adverse events (AEs) were cytopenias and gastrointestinal tract (GI) disorders. This study demonstrates that Idelalisib has potent activity in combination with chemotherapy.
Abstract 4180 gives us data from an additional study, in which Idelalisib is paired with anti-CD20 antibody therapy (Table 1). As in the other studies the cohorts were comprised of a high risk patient population. This was a small phase 1 study with an extension arm, enrolling 40 patients. This study produced some sobering results that remind us how serious a disease aggressive CLL is, and how potent the drugs treating this disease have to be. Notably, 25% of patients did not enter the extension study due to disease progression, 6 patients died. A further 23% did not enter the extension study due to AEs. These data remind us that response rates readout at a specific pre-determined time during the trial, and do not reflect outcomes. Regardless the median PFS and DOR for all patients (N=40) and were 20 and 19 months, respectively. Median overall survival (OS) had not been reached.
The phase 3 study mentioned at the outset, which was stopped early due to significant evidence of clinical benefit, was very similar to, if much larger then, the Phase 1 study presented in abstract 4180. We don’t know much about the trial data yet, but Gilead’s press release states that the “Phase 3 study … evaluating idelalisib in previously-treated … CLL patients who are not fit for chemotherapy will be stopped early  … based on a predefined interim analysis showing highly statistically significant efficacy for the primary endpoint of progression-free survival in patients receiving idelalisib plus rituximab compared to those receiving rituximab alone. The safety profile of idelalisib was acceptable and consistent with prior experience in combination with rituximab in previously treated CLL.”
I think the general takeaway here is that a high proportion of those patients who respond did well over time. The fact that they did so without additional chemotherapy is very encouraging. PFS in either not being reached or is reached at 20 months or so. This suggests that impact on OS will be significant for all of the drug combinations presented. 
 
Additional analyses from Phase 1b and 2 studies were presented in abstract #1632. This abstract presents data comparing responses among CLL patients with high risk prognostic markers (del(17p) or TP53 mutation, del(11q), IGHV mutation and NOTCH1 mutation) to CLL patients without these markers. rrCLL patients given Idelalisib monotherapy or combination therapies responded equally well to treatment regardless of the presence or absence of these critical genetic markers of disease aggressiveness. That is a very important result that suggests great potential for CLL therapy with Idelalisib. The table is below.
 
Note that the response rates in the phase 2 Idelalisib + Rtx trial in previously untreated (i.e. newly diagnosed) patients are quite high, and this is exactly what you want to see as to drug moves to treat patients earlier in their disease course.
Next up is a review the Ibrutinib data in the same disease, and also a quick look at the other therapies in these drug classes.