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Salvage therapies benefit patients with CLL after allogeneic SCT failure
Patients with chronic lymphocytic leukemia or Richter’s transformation who did not respond to or who progressed after allogeneic stem cell transplantation demonstrated benefit from salvage therapies and generally had a favorable prognosis, according to study results.
A fraction of patients with high-risk CLL or Richter’s transformation achieve long-term remission after allogeneic stem cell transplantation (SCT), according to study background. However, previous data indicate patients who initially respond to but eventually relapse after reduced-intensity hematopoietic SCT achieved an effective graft-versus-leukemia response when they received donor lymphocyte infusions and rituximab (Rituxan; Genentech/Biogen Idec).
Zeev Estrov, MD, professor of medicine and director of hematopoiesis research in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues, thus, sought to evaluate outcomes in patients who were not in remission after SCT.
“The life expectancy of patients with refractory CLL is measured in months,” Estrov told HemOnc Today. “Therefore, eligible patients often undergo allogeneic stem cell transplantation. We found that, unlike acute leukemia patients, CLL patients with heavily-pretreated chemotherapy-refractory disease who failed to attain a durable post-allogeneic SCT response experienced a median post-transplant survival of 3 years, indicating that in spite of transplant failure, SCT favorably changed the course of the disease.
“For example, seven patients with fludarabine-refractory disease responded to fludarabine-based therapy after failing transplantation,” Estrov said. “Likewise, in four patients with Richter's transformation who failed allogenic SCT but had no evidence of large cell lymphoma after transplant, the median survival was 31 months, similar to that of post-transplant patients with refractory CLL.”
The researchers analyzed the outcomes of 72 patients (CLL, n = 52; Richter’s transformation, n = 20) who underwent allogenic SCT between 1998 and 2011 and had documented disease progression after the transplant. The median age of patients at the time of transplantation was 58 years (range, 30-72).
Thirty-one percent of the cohort never had a response and 69% had a response but then experienced disease relapse. The median time to relapse was 7 months (range, 2-85).
Patients had received multiple treatment regimens prior to transplantation — 86% had received more than two regimens and 51% had received more than three regimens — and 92% of the population had active disease at the time of transplantation.
Researchers noted that posttransplant treatments among patients with relapsed/refractory disease varied due to a lack of consensus on appropriate regimens in this setting. Forty-four percent of patients received donor lymphocyte infusions. Most patients with CLL received rituximab (40%) or ofatumumab (28%; Arzerra, GlaxoSmithKline), and most patients with Richter’s transformation received a form of chemoimmunotherapy.
For patients with CLL, the 2-year survival rate was 67% and the 5-year survival rate was 38%. For patients with Richter’s transformation, the 2-year survival was 36% and 5-year survival rate was 0%.
Median OS from time of progression was 36 months (95% CI, 24-48) in patients with CLL and 15 months (95% CI, 2-28) in patients with Richter’s transformation.
Researchers noted patients who initially responded to SCT achieved a longer OS than those who never achieved remission (P = .003). The development of acute (P = .04) or chronic (P = .05) graft-versus-host disease (GVHD) also was associated with significantly longer OS.
Results of a multivariate analysis indicated Richter’s transformation (HR = 3.54; 95% CI, 1.74-7.22) and low hemoglobin (HR = 0.76; 95% CI, 0.64-0.9) at the time of the transplant were significant predictors of shorter OS, whereas an initial response to HSCT (HR = 0.35; 95% CI, 0.17-0.71) and chronic GVHD (HR = 0.53; 95% CI, 0.28-1) predicted longer OS.
“Remarkably, GVHD was associated with improved survival, suggesting that the graft-versus-leukemia effect might persist in patients who failed allogenic SCT,” study researcher Uri Rozovski, MD, a post-doctoral fellow at MD Anderson Cancer Center, told HemOnc Today. “While ibrutinib is considered the drug of choice for relapsed/refractory CLL, the beneficial effects of graft-versus-leukemia should be further exploited.”
These results indicate new treatment regimens improve the results of SCT if given in advance of transplant and reduce the risk for complications and disease progression if given after the transplant, Emil Montserrat, MD, a professor of medicine and director of the Institute of Hematology and Oncology at the Hospital Clinic of Barcelona in Spain and Peter Dreger, MD, a clinician in the department of medicine at the University of Heidelberg in Germany and a member of the European Society for Blood and Marrow Transplantation for the Lymphoma Working Party in Paris, wrote in an accompanying editorial.
“The prognosis of patients with CLL progressing after allogenic [SCT] is not necessarily poor,” Montserrat and Dreger wrote. “These patients can gain benefit from both cytotoxic and non-cytotoxic agents in form of high response rates and prolonged PFS and OS.
“In an era of constant progress in the management of CLL, the wise use of current and upcoming treatments, either combined or sequentially, in well-designed and large trials, should continue improving outcomes of patients with the most frequent form of leukemia in Western countries.” – by Anthony SanFilippo
For more information:
Zeev Estrov, MD, can be reached at MD Anderson Cancer Center, 1515 Holcombe Blvd., #853, Houston TX 77030; email: zestrov@mdanderson.org.
Uri Rozovski, MD can be reached at MD Anderson Cancer Center, 1515 Holcombe Blvd., #853, Houston TX 77030; email: urozovski@mdanderson.org.
Disclosure: Estrov and Rozovski report no relevant financial disclosures. Other study researchers report travel accommodations from, consultant/advisory roles with and research funding from Celgene, Gilead, Janssen, Kyowa Hakko Kirin, Noxxon, Pharmacyclics and Sanofi. Montserrat and Dreger report honoraria and travel accommodations from and consultant/advisory and speakers bureau roles with Gilead, GlaxoSmithKline, Janssen, Pharmacyclics and Pfizer.
Perspective
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Until the current publication, little was known about the outcomes of patients treated in the modern era who relapse post-alloSCT. Although this paper is limited by the same problems that affect all retrospective studies, important information is gained from this study.
The authors report the treatment courses and outcomes of 72 patients (52 with CLL, 20 with large-cell transformation) who progress following alloSCT. Most patients relapsed within the first year. For patients with CLL, outcomes were surprisingly good, with 2-year OS of 67% and 5-year OS of 38%.
The majority of patients responded to salvage therapy, and some even responded to multiple lines of salvage therapy. Unlike the often binary responses in acute leukemia, in which patients are either cured by transplant or quickly die from relapse, CLL appears to be a disease in which second chances are possible. This presents an area ripe for investigational strategies that combine transplant immunotherapy with targeted maintenance therapy.
Richter’s syndrome (RS) remains one of the most challenging complications in the management of CLL and an area of great unmet need. Patients in this study with RS had a short OS (median, 15 months) and were less likely to be successfully salvaged. In fact, none of the patients with RS survived to 5 years, compared with the 5-year survival rate of 38% among patients with CLL. In addition, 16 patients (30%) with CLL at the time of transplant developed RS following alloSCT, an important observation that signals a need for improved strategies to manage this usually fatal complication.