NEW YORK—Allogeneic hematopoietic stem cell transplantation (HSCT) still has a role in the treatment of high-risk chronic lymphocytic leukemia (CLL) patients even in the age of targeted therapy, although its role has been diminished by the introduction of novel agents. That was the conclusion of a session on the topic at the Lymphoma and Myeloma International Congress on Hematologic Malignancies here.
“Allogeneic HCT has been considered standard therapy for patients with high-risk CLL for patients who are refractory to purine analogues who have a short response to aggressive chemoimmunotherapy such as fludarabine, cyclophosphamide, and rituximab—less than 24 months—and also show the presence of 17p-TP53 mutations,” said David G. Maloney, MD, PhD, Professor of Medicine in the Division of Oncology at the University of Washington and a Member of Fred Hutchinson Cancer Center.
Early transplantation trials with myeloablative regimens have given way to reduced-intensity regimens with decreased non-relapse mortality. But is allogeneic HSCT still the best treatment for high-risk CLL patients in the era of ibrutinib, idelalisib, and ABT-199? Maloney's short answer was yes.
Panel moderator Richard Furman, MD, Director of the CLL Research Center and Member of the Lymphoma and Myeloma Service at Weill Cornell Medical College, told OT: “Allogeneic HSCT should be reserved for patients with 17p deletions who have lost response to tyrosine kinase inhibitors [TKIs]. When that fails, then think about an allotransplant.”
Furman noted that these patients may need prolonged therapy, and while upfront side effects from novel agents are not severe, after five rounds of therapy, patients are at risk for Richter's transformation and marrow failure. Many of these patients will develop myelodysplastic syndrome and acute myeloid leukemia in the future, “and eventually have an allogeneic HSCT anyway.”
To support his case for allogeneic HSCT, Maloney pointed out that the survival rate for patients with fludarabine-refractory CLL treated by different salvage therapies is generally poor. The overall response rate is about 22 percent and complete response is only about one percent. Almost all patients have disease progression within six months, and median overall survival is one year.
On the other hand, myeloablative allogeneic transplantation for CLL leads to five-year survival rates that range from 33 to 45 percent in clinical trials with patients of median ages in their 30s or 40s— much younger than most CLL patients, Maloney noted.
Older CLL patients need reduced-intensity regimens, and Seattle researchers have developed a protocol of non-myeloablative conditioning using 2 Gy of total body irradiation with or without fludarabine. “This outpatient regimen allows engraftment,” Maloney said. “Granulocyte-colony stimulating factor mobilizes peripheral blood sources, and peripheral blood stem cells are harvested at two days. There is no restriction on CD34 or CD33 numbers, and only minimal hematologic toxicity using matched related donors [MRD], although there is greater toxicity with matched unrelated donors [URD].”
Reliable engraftment occurs with full donor chimerism in more than 95 percent of patients, he said. The graft makes its own space and replaces marrow function. Anti-tumor activity is due to immunologic graft-versus-tumor activity.
Maloney cited the experience with this non-myeloablative conditioning regimen in 128 fludarabine-refractory, advanced CLL patients who received allogeneic HSCT. After a median of 64 months of follow-up, the five-year complete response rate is 52 percent, progression-free survival is 36 percent, and overall survival is 43 percent.
Similar responses have been seen no matter what the type of donor, he said. Other selected trials of reduced-intensity conditioning allogeneic HSCT for CLL show five-year overall survival rates that range from 50 to 63 percent.
Risk factors for this regimen include disease status at HSCT, chromosomal abnormalities, lymph node size, and prior alemtuzumab within 12 months. A multivariate analysis found that lymph node size and prior alemtuzumab within 12 months were the most significant risk factors.
“With CLL risk stratification, we can treat patients better post-allotransplant than before,” Maloney said.
“Non-myeloablative allogeneic transplantation for CLL is an effective therapy for fludarabine-refractory CLL, and appears to be superior to available treatment options. Risk factors for poor outcome include lymph node size more than 5 cm, the presence of comorbidities, and alemtuzumab within 12 months. Other factors—cytogenetics, age, CD38—do not have a significant effect on outcome.”
For allogeneic transplantation for CLL, the major risks are graft-versus-host disease and infection. “A graft-versus CLL effect is active in CLL,” Maloney said. “The lower risk of relapse is in the setting of chronic GVHD. A higher risk of relapse is seen with T-cell depletion and clearance of minimal residual disease.”
Allotransplant has curative potential in high-risk disease, including patients with fludarabine-refractory disease, adverse cytogenetics, and unmutated immunoglobulin genes. It may also provide a better functioning hematopoietic and immune system post-HSCT, Maloney said. The continuing challenge is to determine the optimal time to consider transplant: “Should we transplant prior to the development of bulky disease, or earlier for patients with high-risk disease?” he asked.
The advent of B-cell receptor signaling and inhibition in B-cell malignancies with novel agents has changed the landscape of CLL therapy. For relapsed/refractory CLL, ibrutinib has been shown to be more effective than ofatumumab. “But this is six-month data. We need more follow-up,” he said. A combination of idelalisib and rituximab also appears to be active in the treatment of refractory CLL, leading to improved progression-free and overall survival compared with use of rituximab alone.
“This follow-up is also short, though—1.5 years— but the use of idelalisib and rituximab in relapsed/refractory CLL is warranted. Clearly, these agents are extremely active and promising. Everyone is using these new agents to push transplantation further down the road.”
Novel Classes of Drugs
In a recent article in Blood, lead author Peter Dreger, MD of the Department Medicine at the University of Heidelberg in Germany, noted that current treatment algorithms for high-risk CLL are being challenged by the introduction of novel classes of drugs: “Among them, BCR-signal inhibitors (BCRi) and BCL2 antagonists (BCL2a) appear particularly promising. As a result of the growing body of favorable outcome data reported for BCRi/BCL2a, uncertainty is emerging on how to advise patients with high-risk CLL about indication and timing of HSCT,” he stated.
In this position paper on managing high-risk CLL during the transition to a new treatment era, Dreger and colleagues provided an overview of currently available evidence and theoretical considerations to guide this difficult decision process. “As long as the risks and benefits of different treatment strategies are not settled, all patients with high-risk CLL should be considered for treatment with BCRi/BCL2a.
“For those patients responding to these agents there are two treatment possibilities performing a HSCT and to continue on the novel drug. Individual disease-specific and transplant-related risk factors, along with patient's preferences, should be taken into account when advising one of these treatments over the other,” he stated.
According to the position paper, the paradigm for treating high-risk CLL relapse/refractory patients is to provide novel agents first. If there is no response even after alternative salvage regimen, the recommendation is for HSCT. For responders, the recommendation is HSCT or to continue novel agents.
Factors favoring HSCT are high-risk disease, including high-risk cytogenetics (17p-, TP53 mutation, 11q), and low transplant risk, such as younger patients with no morbidity who have a well-matched donor.
Factors favoring novel agents are lower disease risk patients with no high-risk cytogenetics and no relapse or refractory disease who have a higher transplant risk, such as older patients with significant comorbidity and a mismatched donor.
Discussions with Patients
Oncologists need to discuss certain issues with patients concerning therapy, Maloney said. “These issues should include consideration of HSCT as the treatment of choice for high-risk CLL. This is the only documented curative potential for CLL. B cell tyrosine kinase inhibitors are major advances, and are the best option available to date.
“Responders have two-year overall survival rates of 70 to 90 percent, compared with 60 to 80 percent with HSCT. But long-term results are uncertain. Resistance is possible, and cure is unlikely with novel agents.” Also, the outcome of HSCT post-novel agents is uncertain. HSCT has and early non-relapse mortality rate of 15 to 30 percent in the first two years with a 25 percent risk of chronic GVHD.
“For heavily pretreated patients, we don't know how long we can keep a patient on these drugs. Many patients may be better off with transplantation if they don't develop bulky disease—The new agents are great, but not perfect.”
In conclusion, Maloney said there is still a role for allogeneic HSCT in high-risk CLL: “BCR inhibitors are the best available treatment, but a cure or even complete response seems unlikely. Resistance can arise, and the timing of their use is uncertain. Allogeneic HSCT is still the only curative option. Timing remains controversial, and is patient specific prior to bulky disease.”
He said that at a minimum, he recommends that oncologists discuss HLA typing with their high-risk CLL patients. “I like to do HLA typing just to know if a donor might be available. This might change the patient's priorities.”
He noted that targeted therapy with chimeric antigen receptor (CAR) T cells will also have an impact on HSCT—“and will likely bump transplantation down another notch.”
Furman, however, said he believes that a novel therapy, not CAR T-cell therapy, is the best treatment choice as of now: “For treatment-naïve CLL patients, ibrutinib shows 100 percent PFS at 40 months. CAR T-cell therapy is only 50 percent effective with significant toxicity. Why choose CAR T-cell therapy over a TKI?”
In the question-and-answer period, an audience member asked whether older, healthy CLL patients can undergo allogeneic HSCT. Maloney answered: “My oldest patient had an allotransplant at age 78 and is now 86 years old. We can transplant older patients. Screen them for comorbidity and look at their organ function. Those with a high comorbidity index with have a worse outcome.
“If they are otherwise healthy and in good shape physically, consider searching for a matched donor.”