Photo courtesy of DFCI
NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.
The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients.
“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”
At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.
Rituximab-based therapy
WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.
As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.
So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response.
This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.
“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said.
One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients.
Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy.
“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”
Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.
Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.
And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.
“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.
MYD88 mutations
With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.
About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation.
MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.
MYD88 may also be important in predicting who will respond to drugs like ibrutinib.
CXCR4 mutations
Mutations in CXCR4 are the second most common mutation in WM.
Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.
This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling.
Ibrutinib therapy
With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance.
They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.
Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.
“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.”
The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort.
The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).
The progression-free survival at 2 years was 69% and overall survival was 95%.
At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia.
And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated.
Response to ibrutinib by mutation status
The overall response rate was 90% for all patients, but there were differences according to mutation status.
Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.
Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well.
If they also had a CXCR4WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%.
“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.
Patients with a CXCR4 mutation also respond more slowly than those without the mutation.
This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.
“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said.
“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.”
Ibrutinib in rituximab-refractory patients
A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.
The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.
Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.
Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.
The study was just accepted for publication in Lancet Oncology.
IRAK inhibition
Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.
So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.
Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.
“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”
Resistance to ibrutinib
Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds.
These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation.
C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.
So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.
Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase.
Other drugs being developed for WM include:
- Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
- Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
- Agents that block CXCR4 receptor signaling, such as ulocuplomab
- The BCL2 inhibitor venetoclax
- The CD38-targeted agent daratumumab.
Current treatment strategies
Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.
For patients with mutated MYD88 and no CXCR4 mutation:
- If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
- If patients have bulky disease, a combination of bendamustine and rituximab may be used.
- If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
- If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.
For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions.
To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib.
The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.
“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”
Bendamustine- or bortezomib-based therapy is effective in this population and can be considered.
In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.
