Developments in Hematologic Cancers Include New Considerations in Treating Challenging Leukemias and Multiple Myelomas


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Speakers at the National Comprehensive Cancer Network (NCCN) 7th Annual Congress on Hematologic Malignancies reviewed the current standard of care for various hematologic cancers and explored new concepts in treatment. Below are highlights from presentations on chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and multiple myeloma.

Suboptimal Response in CML

For the first time, discussion of suboptimal response has been incorporated into the NCCN Chronic Myelogenous Leukemia Guidelines. Definitive treatment options are not recommended for patients in this subgroup, but the guidelines acknowledge that these patients “require careful monitoring and may benefit from alternative treatment options.”

Neil Shah, MD, PhD, UCSF Helen Diller Family Comprehensive Cancer Center, explained that the term “suboptimal response” is derived from the European LeukemiaNet guidelines. Patients with a suboptimal response to imatinib (Gleevec) may still have a substantial long-term benefit from treatment with dose-escalated imatinib or another approved tyrosine kinase inhibitor such as dasatinib (Sprycel), nilotinib (Tasigna), and the recently FDA-approved bosutinib (Bosulif) but have a reduced likelihood of optimal response.

Suboptimal responders at 3 and 12 months should be switched to a different tyrosine kinase inhibitor, Dr. Shah said. At 3 months, suboptimal response refers to lack of any cytogenetic response. At 12 months, suboptimal response is defined as a partial, but not complete, cytogenetic response (and less than a partial response is considered “failure” by the European LeukemiaNet guidelines).

In the early tyrosine kinase inhibitor experience, the 8-year overall survival rate on imatinib treatment was 85%. The majority of events related to disease progression or death occurred during the first 3 years of treatment, Dr. Shah said. Experience with imatinib showed that in general, the deeper the response, the better the long-term outcome. Patients with deep cytogenetic responses have better outcomes than those without a cytogenetic response. “Patients with 3-log reductions may also do better than those with lesser molecular responses, but this is an emerging concept,” he said.

About 30% of patients fail to achieve a complete cytogenetic response at 12 months on imatinib. These patients should preferably be switched to a different tyrosine kinase inhibitor.

Mutational testing is not recommended at baseline prior to treatment initiation, because drug-resistant mutations develop on treatment. The current recommendation is to perform mutational testing on a patient who fails to meet the 3-month, 12-month, or 18-month milestone. Mutations should also be assessed in patients with loss of response or disease progression at any time

Thus far, all approved therapies fail to overcome resistance due to the T315I mutation. However, ponatinib, an investigational tyrosine kinase inhibitor in phase III trials, appears to overcome resistance to T315I, and this drug should be approved early in 2013, he said.

Overcoming Resistance in CML

Another change in the 2012 version of this algorithm is incorporation of molecular testing at the 3-month treatment milestone for patients who fail to meet the threshold of BCR-ABL ≤ 10% on the International Scale on polymerase chain reaction testing.

About 50% of patients with CML who develop resistance to tyrosine kinase inhibitors present a mutation in the abl kinase, and although more than 100 have been described, only 14 of them account for about 80% of all treatment-related mutations, explained Javier Pinilla-Ibarz, MD, H. Lee Moffitt Cancer Center, Tampa, Florida.

The current NCCN recommendation is to perform BCR-ABL mutational analysis when patients fail to achieve treatment milestones. Higher-dose imatinib is no longer widely used to treat patients with suboptimal response or failure; instead, second-line therapy with a different tyrosine kinase inhibitor is recommended.

In specific cases, some mutations may respond better to one of the available tyrosine kinase inhibitors. While V299L, T315A (different from T315I), and F317L/V/I/C mutations are better treated with nilotinib, Y253H, E255K/V, and F359V/C/I are more responsive to dasatinib. Bosutinib may also have better efficacy in cases of F359V/C/I and F317L/V/I/C mutations. As noted earlier, experts in the field are hoping that the investigational drug ponatinib will fulfill its promise of overcoming the ubiquitous mutation T315I (different from T315A), which is resistant to all the currently available drugs.

Data from the PACE trial of ponatinib recently presented at the ASCO Annual Meeting and the European Hematology Association Annual Congress are promising, showing a high complete cytogenetic response rate in heavily pretreated patients, including those who harbor the T315I mutation. The overall complete cytogenetic response rate in patients with chronic phase was 44%, which Dr. Pinilla-Ibarz called “remarkable.”

There is still a role for allogeneic stem cell transplantation in CML, he continued. For imatinib failure in accelerated or blast phase, he advised using a new tyrosine kinase inhibitor as a bridge to minimal residual disease and then going to stem cell transplantation as soon as possible.

For patients with T315I mutation in any phase, ponatinib (once it is approved by FDA) should be used as a bridge to minimal residual disease, and allogeneic stem cell transplantation should be performed until we have longer follow-up with this drug.

Relapsed/Refractory ALL

Hematopoietic stem cell transplantation remains the standard of care for relapsed/refractory acute lymphoblastic leukemia, explained Joseph Alvarnas, MD, Associate Clinical Professor at City of Hope Comprehensive Cancer Center in Duarte, California.

Experience in treating relapsed/refractory ALL shows that patients should be risk-stratified at the time of diagnosis and treated accordingly, and that transplant should be performed after the first complete remission is achieved. Another lesson from the experience at City of Hope is that unrelated donor transplants have similar outcomes as related donor transplants.

“Don’t let the lack of sibling donor keep you from moving on to transplant,” Dr. Alvarnas told listeners.

 Several new agents under study may improve outcomes in relapsed/refractory ALL. Nelarabine (Arranon), a prodrug of ara-G, and clofarabine (Clolar), a second-generation purine nucleoside analog, have had encouraging activity in phase II trials of patients with relapsed/refractory ALL.

Each drug has toxicities. With nelarabine, neurologic toxicity is the key dose-limiting toxicity, and other significant toxicities include cytopenia, gastrointestinal effects, and pyrexia. Toxicities of clofarabine include elevations of liver enzymes, febrile neutropenia, skin rash, and cytomegalovirus reactivation.

Dr. Alvarnas said that researchers are working on finding a monoclonal antibody in ALL that parallels rituximab (Rituxan) in lymphoma. Blinatumomab (AMG 103) and inotuzumab ozagamicin are active in relapsed/refractory ALL and well tolerated in preliminary studies.

Blinatumomab is the first in a new class of agents called bi-specific T-cell engager (BiTE) antibodies that harness T cells to destroy the tumor cells. A phase II trial in relapsed/refractory ALL found that 26 of 36 patients achieved complete remission (72%), and median survival was 9 months (range, 8.2–15.8 months).4

Inotuzumab ozogamicin is an anti CD22 antibody conjugated with calicheamicin that induces double-stranded DNA breaks. A phase II trial of 40 patients with relapsed/refractory ALL treated with a median of two courses of therapy showed a complete remission rate of 56%; 70% of responders were alive at 6 months following therapy, and 12 patients went on to allogeneic stem cell transplant.5 Grade 3 or 4 fever was reported in nine patients and grade 3 hypotension in one patient.

Overcoming Genetic Transformation in Multiple Myeloma

Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, Boston, emphasized two main points in his presentation.6 The first is that a triple-drug combination incorporating a proteasome inhibitor and an immunomodulatory drug for induction therapy is the best hope for achieving high frequency and extent of response in newly diagnosed multiple myeloma. After high-dose therapy and stem cell transplantation, consolidation and maintenance therapy using these drugs can prolong progression-free survival.

The second point he emphasized was that the risk of second malignancies should not dissuade oncologists from treating patients with lenalidomide (Revlimid) maintenance therapy. Dr. Anderson recommended a similar strategy in patients with newly diagnosed multiple myeloma who are not transplant candidates—that is, incorporating new drugs for induction therapy and maintenance therapy to prolong survival.

One of the hurdles in treating multiple myeloma is its genetic complexity. At diagnosis, many mutations and other abnormalities are present, and at relapse new mutations arise, copy numbers changes, and translocations and other changes occur. He said that he is “passionate” about “not allowing this genetic evolution to occur in this hideously complex disease” and recommended a three-drug regimen incorporating novel agents as induction therapy followed by maintenance therapy.

As the number of new drugs for multiple myeloma has increased, various combinations have been studied as treatment of newly diagnosed patients using drugs like bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide, and dexamethasone. Studies to date have shown that a four-drug combination was not an improvement over triple-drug therapy.

The favored induction regimen at Dana-Farber Cancer Institute is RVD (lenalidomide, bortezomib, and dexamethasone), Dr. Anderson said. Building on success with RVD, the recently approved proteasome inhibitor carfilzomib substituted for bortezomib in that regimen may further improve outcomes, he noted. He was enthusiastic about results of a phase II study using the CRD regimen (carfilzomib, lenalidomide, dexamethasone), which were presented at the 2011 American Society of Hematology Annual Meeting.7

An oral proteasome inhibitor, MLN9708, is in clinical trials. If this drug is approved, then an all-oral three-drug combination would be possible, Dr. Anderson said. ■

Disclosure: Drs. Shah, Pinilla-Ibarz, Alvarnas, and Anderson reported no potential conflicts of interest.

References

1. Shah NP: How to respond to a suboptimal response in CML (and by the way, what is a suboptimal response?). NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012.

2. Pinilla-Ibarz J: Overcoming resistance to TKI in Ph+ leukemias. NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012.

3. Alvarnas JC: New approaches to the management of relapsed/refractory acute lymphoblastic leukemia. NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012.

4. Topp M, Goekbuget N, Zugmaier G, et al: Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. 2012 ASCO Annual Meeting. Abstract 6500. Presented June 4, 2012.

5. Jabbour E, O’Brien SM, Thomas DA, et al: Inotuzumab ozogamicin (IO; CMC544), a CD22 monoclonal antibody attached to calicheamycin, produces complete response (CR) plus complete marrow response (mCR) of greater than 50% in refractory relapse (R-R) acute lymphocytic leukemia (ALL). 2011 ASCO Annual Meeting. Abstract 6507. Presented June 6, 2011.

6. Anderson KC: Evidence-based treatment of newly-diagnosed multiple myeloma: Does one treatment fit all? NCCN 7th Annual Congress: Hematologic Malignancies. Presented September 14-15, 2012.

7. Jakubowiak A, Dytfeld D, Jagannath S, et al: Final results of a frontline phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in multiple myeloma (MM). 53rd ASH Annual Meeting. Abstract 631. Presented December 12, 2011.



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