Objectives: Our aim was to compare patients with high-risk chronic lymphocytic leukemia referred to our transplant center who underwent allogeneic stem cell transplant with those who did not receive this treatment. Factors compared included demographics, clinical characteristics, and survival rates in the novel targeted therapy era.

Materials and Methods: All 33 patients with high-risk chronic lymphocytic leukemia who were referred to the hematopoietic stem cell transplant center were enrolled in this retrospective, single-center nonrandomized study. Outcomes of patients who received allogeneic stem cell transplant were compared with those of nontransplant patients. Chemoimmunotherapy and ibrutinib were given when indicated. Factors related to overall and progression-free survival were assessed.

Results: Thirteen patients underwent allotransplant, and transplant was not done in 20 patients for various reasons. Demographic and clinical features of the transplant and nontransplant groups were similar. The estimated cumulative overall survival was 72.6 ± 15 and 84.3 ± 13 months in the nontransplant and transplant groups, respectively. The 5-year overall and progression-free survival rates in the transplant and nontransplant groups were 57.3%/36.0% and 40%/20.6%, respectively. In the nontransplant group, overall survival of those who used ibrutinib was longer than overall survival in patients in the transplant group who used the same drug, but the difference was not statistically significant. Although not significant, overall survival in patients who did not use ibrutinib was longer in the transplant group than in the nontransplant group. Cox regression analyses showed that transplant, relapse, and Binet stage were independent predictors of overall survival.

Conclusions: In patients who do not use ibrutinib, allogeneic stem cell transplant improved survival compared with nontransplant patients. Addition of ibrutinib provided comparable life expectancies, showing that allogeneic stem cell transplant and ibrutinib may have complementary roles. Transplant is still an independent predictor of overall survival.

Key words : Adult leukemia, Allogeneic stem cell transplant, Ibrutinib, Survival

Introduction

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adulthood1; recently, with the introduction of novel targeted therapies, there has been significant progress in the outcome of this disease. The estimated survival from first diagnosis ranges from 18 months to more than 10 years,² and the 5-year overall survival (OS) is estimated to be 84%.³ Chronic lymphocytic leukemia is a heterogeneous disorder, and treatment strategies vary greatly depending on the disease risk group and whether the disease is symptomatic. Although most newly diagnosed patients can be treated with chemoimmunotherapy with good responses, in some patients with high risk, the disease may progress rapidly with a fatal outcome within 2 to 3 years of diagnosis.^4,5 Therefore, allogeneic hematopoietic stem cell transplant (allo-SCT) is considered to be the choice of treatment to provide long-term disease control in patients with high-risk disease, such as refractory to or relapsing within 2 years after purine-based analogs, or poor prognostic cytogenetics, including 17p deletion, p53 mutation, or 11q deletion.^6,7 In 2007, the European Society for Blood and Marrow Transplantation (EBMT) reported consensus recommendations to outline the criteria for allo-SCT.⁸

In recent years, the B-cell receptor (BCR) pathway inhibitors (ibrutinib, idelalisib) and B-cell lymphoma 2 inhibitors (venetoclax) have been shown to be effective in the treatment of high-risk CLL patients and have become available in many clinics. The National Comprehensive Cancer Network identified ibrutinib and venetoclax as the preferred agents for patients with relapsed/refractory CLL, especially those with 17p deletion.⁹ This has also been supported in a recent meta-analysis.¹ The success of these agents has challenged the appropriateness of those recommendations and made it more difficult to assess who should be considered for allo-SCT and when in the treatment course.

There are no randomized controlled trials com­paring outcomes of allo-SCT with conventional chemotherapy, immunochemotherapy, or novel nonchemotherapy-containing regimens, and there are few nonrandomized trials that have compared outcomes of patients with allo-SCT and no transplant.^10-12 All these studies had been conducted prior to the availability of novel agents. In this nonrandomized study, we aimed to compare patients referred to our transplant center who underwent allo-SCT with those who did not. Factors that were compared were demographics, clinical charac­teristics, and survival rates.

Materials and Methods

All patients who were diagnosed with CLL and referred to the Baskent University Adana Hospital Department of Hematology Hematopoietic Stem Cell Transplantation Center between January 2007 and March 2019 were enrolled in this retrospective, single-center nonrandomized study. Medical records were obtained from the hospital’s electronic database, patient files, and standard forms that were created for transplant patients in the Nucleus Electronic Data Management System (version 9.3.39; Monad Software Co., Ankara, Turkey). The forms were in accordance with the Joint Accreditation Committee: International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation Accreditation criteria (JACIE). A data audit group checked all data. The study received approval from our institution’s ethics committee (KA19/274).

From our database, we selected consecutive patients who (1) had a diagnosis of CLL, (2) had been referred for allo-SCT, and (3) had undergone allo-SCT or given chemotherapy without transplant for any reason. A total of 33 patients who provided written informed consent according to institutional policy fulfilled these criteria and were included in the study.

As a JACIE accredited transplant center, early-stage asymptomatic CLL patients are followed with a “watch and wait” approach. Treatment is initiated when at least 1 of the following clinical situations are present: hemoglobin < 10 g/dL or platelet count < 100 × 10⁹/L, massive splenomegaly, massive or progressive lymphadenopathy, an increase of lymphocytes of ≥ 50% over a 2-month period or lymphocyte doubling time of < 6 months, autoimmune complications of CLL that are not responsive to steroids, presence of B symptoms, and extranodal involvement.¹³ In standard-risk patients, induction therapy is chemoimmunotherapy (fludarabine, cyclophosphamide, rituximab or bendamustine, rituximab in those < 65 years). In TP53 disrupted patients, ibrutinib is directly initiated when patients are > 70 years; when they are ≤ 70 years old, permission is necessary from the Ministry of Health for ibrutinib as a first-line therapy.

Clinical response was based on results of perip­heral blood, bone marrow, and imaging studies (ultrasonography and/or computed tomography); responses were assessed every 3 to 6 months. Response to treatment was classified as partial or complete remission or progressive disease based on the National Cancer Institute-sponsored Working Group on CLL guidelines.¹³ Briefly, complete remission requires absence of lymphadenopathy, hepatomegaly, or splenomegaly by physical exa­mina­tion and appropriate radiographic imaging. There should be no constitutional symptoms. Polymorphonuclear leukocyte count should be ≥ 1500/μL, platelet count should be > 100 000/μL, hemoglobin level should be > 11 g/dL, bone marrow aspiration should be normocellular for age, and there must be less than 30% of nucleated cells being lymphocytes for a period of at least 2 months. Partial remission is the state when there is a ≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value and ≥ 50% reduction in lymphadenopathy and/or ≥ 50% reduction in the size of the liver and/or spleen. In addition, polymorphonuclear leukocyte count, platelet count, and hemoglobin level must be ≥ 1500/μL, > 100 000/μL, and > 11 g/dL, respectively, or there must be 50% improvement over baseline for each of these parameters without transfusions. Progressive disease is characterized by at least 1 of the following: (1) ≥ 50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive determinations 2 weeks apart (at least 1 node must be ≥ 2 cm) and appearance of new palpable lymph nodes; (2) ≥ 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin and appearance of palpable hepato­megaly or splenomegaly, which was not previously present; (3) ≥ 50% increase in the absolute number of circulating lymphocytes to at least 5000/μL; and (4) transformation to a more aggressive histology (eg, Richter syndrome).13 In our center, patients were considered for allo-SCT if they met at least 1 of the 3 EBMT consensus criteria. The criteria included symptomatic disease with a p53 abnormality, fludarabine-refractory disease, and early relapse after intensive pretreatment.⁸

Having a full HLA-matched related donor and good Eastern Cooperative Oncology Group perfor­mance status (0-1 status) were the additional criteria. Patients who relapsed within 30 days of transplant and/or those with unavailable relapse date or lost to follow-up were excluded. Allogeneic stem cell transplant was performed in 13 patients. Full HLA-matched related donors were identified for all the patients, and stem cells were obtained from peripheral blood. The conditioning regimen was myeloablative. Busulfan 9.6 mg/kg, fludarabine 125 mg/m2, and antithymocyte globulin 30 mg/kg were administered. Granulocyte colony-stimulating factor (2 × 5 mg/kg for 4 days) was given subcutaneously to donors. The peripheral stem cells that were collected from donors were infused without any manipulation. Cyclosporin was started on day -2 of transplant at 3 mg/kg/day, and methotrexate was given at 8 mg/m2 on day +2, +4, and +8 for graft-versus-host disease (GVHD) prophylaxis. In addition, cyclophosphamide was administered on days +3 and +4 for a total dose of 60 mg/kg because of high GVHD risk in CLL. In 35% of the 20 nontransplant patients, a full HLA-matched related donor could not be found, and the remaining 13 patients did not want to undergo allo-SCT.

The Rai14 and Binet staging systems¹⁵ were used to allocate patients into good, intermediate, and poor prognosis groups. In addition, cytogenetic analysis was performed with interphase fluorescence in situ hybridization (FISH) studies. Briefly, the FISH panel consists of LSI TP53/CEP17, LSI D13S319 (13q14.3), LSI ATM (11q22)/Cep 11(D11Z1) (DC), D6Z1/LSI MY8 (6q23), and Cep 12 SO, LSI IGH@(14q32)/CCND1-XT (11q13) (DC/DF). Some patients brought their FISH study results, which had been performed in other centers, including Zap70.

Chemoimmunotherapy consisted of fludarabine, cyclophosphamide, rituximab (RFC) or fludarabine and rituximab. Determination of lymphocytosis, palpable lymph nodes, and/or hepato/splenomegaly after 6 months from discontinuation of first-line therapy warranted relapse investigation. In such cases, bone marrow assessment and computed tomography or positron emission tomography scan were used for comprehensive assessment. The patient’s cytogenetics were reevaluated with CLL FISH panel. When a relapse was diagnosed, rituximab and bendamustine (RB) or RFC or ibrutinib was given to the nontransplant group and rituximab and donor lymphocyte infusion (R-DLI) and ibrutinib were given to the transplant group.

Minimal residual disease (MRD) analysis was performed using the blue (wavelength = 488 mm) and red (wavelength = 633 mm) lasers of an 8-parameter Becton Dickinson FACS CANTO II device (BD Bioscience, San Jose, CA, USA). The single-tube assay incorporates 8 antibodies, namely, CD45, CD19, CD5, CD20, CD22, CD23, CD200, and CD38. The MRD bone marrow-positive cutoff was 0.1%. All antibodies were supplied by BD Bioscience.

The diagnosis and grading of acute GVHD were performed according to the consensus conference on acute GVHD.16 Chronic GVHD was diagnosed and graded based on published criteria.¹⁷

The main outcome to be assessed was OS, which was calculated from the time of transplant in the allo-SCT group and initiation of chemoimmunotherapy in the nontransplant group to death from any cause or the last follow-up. Progression-free survival was calculated starting from transplant or chemoim­munotherapy to development of any relapse. Fluda­rabine refractoriness was considered when there was no response or relapse within 6 months after the last cycle.

Statistical analyses
Statistical analysis was performed with SPSS version 22 (demo version; IBM). Nominal data are shown as percentages, normally distributed continuous data are shown as means ± standard deviation, and nonnormally distributed continuous data are shown as median (minimum to maximum or range). Mean survival time is shown as mean ± standard error (95% confidence interval [95% CI]). Chi-square, t test, and Mann-Whitney U tests were used where appropriate. Kaplan-Meier analysis was performed for survival analysis. Comparisons between groups with respect to survival were performed using the log-rank test. Cox regression analysis was used to determine the independent predictors of relapse and OS. A P value of ≤ .05 was considered significant.

Results

Clinical data are presented for nontransplant patients in Table 1 and for transplant patients in Table 2. In the nontransplant group, chemoimmunotherapy RFC was initiated as first-line therapy in 17 patients (85%); rituximab and bendamustine and rituximab and cyclophosphamide were given to 2 patients, and ibrutinib alone was initiated in 1 patient (Table 1). Twelve patients (60%) had cytogenetic findings, with trisomy 12 and 17p deletion being the most common (Table 1). Seven patients (35%) received ibrutinib, with 5 patients (25%) initiated later during the course of the disease after relapse, in 1 patient (5%) because he could not tolerate RFC treatment, and in 1 patient as first-line therapy and continued. One patient died due to sepsis in month 5 of rituximab and bendamustine therapy.

In the transplant group, 10 patients (76.9%) had cytogenetic findings, with 17 p deletion again being the most common anomaly (Table 2). Relapse was seen in 8 patients (61.5%), and ibrutinib was given to 4 (30.8%) of these patients after DLI or R-DLI therapies (Table 2). A second allo-SCT was done to 1 patient (patient 4 in Table 2). Acute grade 3-4 GVHD developed in 1 patient, and chronic severe GVHD developed in 3 patients. At the time of allo-SCT, 6 patients (46.2%) had a complete response, 6 patients (46.2%) had a partial response state, and 1 patient (7.6%) was refractory. Four patients died during the study period. At the present time, 8 patients (88.9%) are in complete remission and 1 patient (11.1%) is in partial remission (Table 2). The patient in partial remission had developed Richter transformation after allo-SCT and is still using ibrutinib (patient 4 in Table 2). Patient 3 in Table 2 had developed Richter transformation before allo-SCT and died 3 years after transplant.

There were no significant differences with respect to demographic and clinical features between the transplant and nontransplant groups except for the time from diagnosis to treatment, which was much shorter in the transplant group (Table 3). The distribution of risk status according to Rai and Binet classifications was also similar (P = .217 for Rai, P = .313 for Binet; Tables 1 and 2).

The estimated cumulative OS was 72.6 ± 15 months (95% CI, 43.1-102) and 84.3 ± 13 months (95% CI, 58.9-109) in the nontransplant and transplant groups, respectively (P = .563, log-rank chi-square = .334) (Figure 1). The 2- and 5-year OS rates were 90% and 40% in the nontransplant group; rates in the transplant group were 91.7% and 57.3%, respectively (Figure 1). When OS was compared between the groups with respect to ibrutinib use, the estimated cumulative OS of the nontransplant group who used ibrutinib was longer than OS in the transplant group who used the same drug; however, this difference was not statistically significant (93.0 ± 20.8 vs 59.0 ± 11.9 mo; P = .820, log-rank chi-square = .052) (Figure 2).

The comparison between the nontransplant and transplant patients who did not use ibrutinib with respect to the cumulative OS is depicted in Figure 3. The mean estimated cumulative OS in patients who did not use ibrutinib was longer in the transplant group than in the nontransplant group; however, this difference was not significant (86.0 ± 17.5 vs 47.4 ± 6.1 months; P = .820; log-rank chi-square = .052) (Figure 3).

The mean estimated progression-free survival was 56.5 ± 9.7 months (95% CI, 50.3-57.3) and 54.9 ± 12.3 months (95% CI, 19.1-72.9) in the nontransplant and transplant groups, respectively, with no significant difference (P = .810, log-rank chi-square = .058) (Figure 3). The 2- and 5-year cumulative progression-free survival rates were 80.2% and 20.6% in the nontransplant group and 83.3% and 36.0% in the transplant group, respectively (Figure 4).

Independent predictors of OS were assessed using Cox regression analysis (Table 4). Age at treatment, transplant, relapse, ibrutinib treatment, Rai and Binet stages, and lactate dehydrogenase level at initiation of treatment were included in the model. Transplant, relapse, and Binet stage were found to be independent predictors of OS (Table 4). Allogeneic stem cell transplant significantly improved and development of relapse and being in Binet stage C significantly decreased OS (Table 4).

Discussion

Allogeneic stem cell transplant is still considered the only treatment with curative potential in patients with CLL, especially in high-risk patients, with 5-year OS ranging between 41% and 63%.18-21 Despite decreased nonrelapse mortality rates in recent years with proper patient selection and improved supportive care, rates are still considerably high, ranging from 15% to 30% during the first 2 years after transplant.22 Efforts to improve outcomes have led to development of novel targeted agents, and the success of these agents in treating high-risk disease has challenged the appropriateness of 2007 EBMT consensus recommendations. To assess the role of allo-SCT for CLL in the novel agent era, we compared outcomes (OS and progression-free survival) of high-risk CLL patients who received allo-SCT and patients to whom transplant was indicated but could not be done for various reasons.

The estimated cumulative OS was found to be improved 11.7 months in patients with allo-SCT compared with the nontransplant patients, although this difference was not statistically significant. The 5-year OS was 57.3% in the transplant group versus 40% in the nontransplant group. Ibrutinib was administered in 35% and 30.8% of patients in the nontransplant and transplant groups, respectively, and patients who used ibrutinib in the nontransplant group had better estimated cumulative OS versus patients who used the same drug in the transplant group; however, this difference was again not statistically significant. Patients who did not use ibrutinib in the transplant group had a better estimated cumulative OS than patients who did not use the drug in the nontransplant group. These results demonstrated that transplant seems to improve survival when there is no additive novel therapeutic agent; in addition, when these agents are included during the course of the disease, survival of the nontransplant group became comparable with the transplant group.

There are no prospective randomized controlled trials that have compared allo-SCT with other nontransplant strategies, especially in the novel targeted therapy era. In the few nonrandomized retrospective studies that have been conducted before the availability of new drugs, allo-SCT demonstrated a better overall life expectancy.^10-12 In their retrospective donor versus no donor comparison study, Herth and colleagues concluded that allo-SCT might have the potential to improve the natural course of outcomes in patients with poor risk CLL as defined by the EBMT criteria.¹⁰ Poon and colleagues studied outcomes of CLL patients with 17p deletion and showed that 2-year OS rate in patients with allo-SCT was 64% compared with 25% in patients without SCT.¹¹ Because there are no prospective randomized studies, Kharfan-Dabaja and colleagues conducted a Markov decision analysis that aided in decision making when uncertainty is present or when the superior treatment is unknown. In their model, they demonstrated the superiority of reduced toxicity allo-SCT over nontransplant therapies for relapsed/refractory CLL.¹² Our study was conducted in patients who could have the chance to get ibrutinib when indicated. The results showed that the transplant and nontransplant groups had similar life expectancies. In fact, although not significant, OS was better in nontransplant patients who used ibrutinib than in transplant patients who used the same drug; in patients who did not use ibrutinib, OS was better in transplant patients than in nontransplant patients. This shows the positive contribution of ibrutinib to the course of the treatment.

After the demonstration of an OS advantage of RFC over fludarabine and cyclophosphamide, RFC has become the gold standard regimen for initial therapy in younger, fit CLL patients.²³ However, it was observed that a subset of high-risk patients was either refractory to initial chemoimmunotherapy or relapsed quickly without being able to maintain a durable disease control. Thus, high-risk CLL patients who achieved a good-quality remission have been referred for SCT. However, the advent of highly efficacious novel agents has called into question the existing paradigm of when to incorporate allo-SCT in the management of CLL. Ibrutinib is one of these agents and is a potent, orally administered covalently binding, irreversible, and specific inhibitor of Bruton’s tyrosine kinase, which is a key signaling molecule upstream in the BCR pathway that is activated in CLL.²⁴ At 12 and 26 months, the OS rates in patients who used ibrutinib were reported to be 90% and 83%, respectively, in different studies.^25,26 The response rate in relapsed/refractory CLL patients was reported to be 80%, and the 2-year survival was 74%.²⁷ Studies showed that high-risk prognostic features did not impact response rates. In patients with 17p deletion, the efficacy of ibrutinib was significantly better than conventional therapies but was still inferior to patients without 17p deletion,²⁶ with a survival rate of 65% at 30 months.28 In our study, the 1- and 5-year OS rates in nontransplant patients who used and did not use ibrutinib were 100%/66.7% and 85%/28%, respectively (log-rank chi-square = 3.48, P = .06), which is comparable with the literature.

The main concern about new agents is that, although response rates are considerably high, relatively few patients achieve complete remission (MRD negative state) and the remaining CLL cells can acquire resistance mutations, possibly leading to dismal outcomes.²⁹ Ibrutinib has high response rates with relatively long remission duration; however, complete remissions are rare, and 17p deletion is still a cause of lower response. In addition, the long-term outcomes are not yet known with these agents, making it challenging to have universal guidelines for when to consider allo-SCT in CLL. Allogeneic stem cell transplant has some known benefits. Briefly, graft-versus-leukemia effects after allo-SCT can provide cure in a subset of patients. It overcomes the poor prognostic impact of initial chemoimmunotherapy refractoriness and high-risk cytogenetic features, including 17p deletion.21 However, there are still unanswered questions like how effective allo-SCT is after exposure to the novel agents and whether allo-SCT outcomes will be improved by the novel agents when they are used as a maintenance strategy after allo-SCT. In the present study, allo-SCT, but not ibrutinib use, was found to be an independent predictor of OS in high-risk CLL patients in the studied patient population with a hazard ratio of 0.123 (95% CI, 0.017-0.892). Ibrutinib was initiated in 4 relapsed patients after allo-SCT, and 2 died after 30 and 12 months from the initiation of ibrutinib (Table 2). The 2 surviving patients have been using ibrutinib for 52 months (has 17p deletion) and 42 months without any progression. These results thus show that allo-SCT and ibrutinib may have comple­mentary roles in high-risk CLL patients. This has been supported by preliminary clinical results that suggested ibrutinib treatment may improve clinical CLL relapse after allo-SCT without eliciting GVHD.30 Therefore, targeted therapy seems to have a potential to improve transplant-associated outcomes.

Progression-free survival in the allo-SCT group was 83.3% at 2 years and 36% at 5 years, which is comparable with other studies.^18-20,31 These rates were 80.2% and 20.6% in the nontransplant group. Transplant was not an independent predictor of progression-free survival (data not shown), and, because ibrutinib was only initiated after progression in the present study, its effect on progression-free survival could not be assessed.

Relapse and Binet stage of the disease at the time of treatment were found to be independent predictors of OS. Development of relapse and being in Binet stage C decreased OS, with hazard ratios of 6.67 and ^11.19, respectively. In relapsed CLL patients, a comprehensive assessment should be carried out, including a bone marrow aspirate/biopsy and computed tomography scans of the chest, abdomen, and pelvis. If there is suspicion of Richter transformation, a positron emission tomography scan should be considered. Also, these patients should have a CLL FISH panel, and, at minimum, TP53 mutation status should be reanalyzed before start of therapy. In these patients, novel agents must be mainly preferred; however, chemoimmuno­therapy may also be considered when there is patient preference, prohibitive cost of the novel agents, significant comorbidities that preclude the use of novel agents, or if the patient has had a long (> 3- to 5-year) remission duration after the first therapy.¹ The Binet¹⁵ and Rai¹⁴ classification systems are used to allocate patients into good, intermediate, and poor prognostic groups; however, neither system succeeds in predicting disease progression at an early stage for an individual patient. In the present study, being in Binet stage C was found to predict decreased OS. Binet stage, but not Rai, was also shown to be an independent prognostic indicator in CLL patients in other studies.³²

The main strength of this study is the patient sample meeting homogeneous criteria for high-risk disease. There were no differences with respect to demog­raphic and clinical features between the groups. In addition, the study was conducted in an experienced, accredited transplant center with outcomes similar to those reported in the literature. There are several limitations of the study. Along with drawbacks related to the retrospective design, the sample size was relatively small and only ibrutinib was used as a novel agent. The outcomes with other novel agents were unanswered.

This study cannot answer the question of when to proceed to allo-SCT in patients responding to a BCR pathway inhibitor. Randomized prospective studies that compare novel agents and allo-SCT may provide an answer. Until that time, the decision should be individualized and depend on the estimated transplant risks and the patient’s desires.³³ It is obvious that outcomes of both allo-SCT and novel therapies must be weighed against their advantages and disadvantages, including morbidity, mortality, response, and duration of response. In our belief, in patients with 17p deletion, ibrutinib therapy should be initiated as a first-line therapy and allo-SCT may be considered whenever the patients are refractory to ibrutinib or when there is relapse.

In conclusion, we found that, in patients who do not use ibrutinib, allo-SCT improved survival com­pared with nontransplant patients. Addition of ibrutinib provided comparable life expectancies, showing that allo-SCT and ibrutinib may have complementary roles. Transplant is still an indepen­dent predictor of OS, and optimal use of targeted novel agents before or after transplant is yet not known and is a field of investigation.

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