Disease Status and Clinical Outcome Definitions
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in United States and has a rapidly evolving treatment paradigm. Two phase III clinical trials demonstrated that inhibition of Burton’s tyrosine kinase (BTK) with ibrutinib results in extended progression free survival (PFS) as a first line agent when compared to standard chemoimmunotherapy in both young and older patients. Similar PFS improvement has been noted in phase III trial with the first line use of B-cell lymphoma 2 (BCL2) inhibitor venetoclax. Outcomes have also improved for relapsed/refractory CLL patients failing first line treatment with the use of phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib or venetoclax. The advent of these novel pathway inhibitors (PI) have reduced the number of CLL patients undergoing allogeneic blood or marrow transplantation (alloBMT) across Europe and United States. However, alloBMT remains the only CLL treatment modality with proven curative potential. AlloBMT is recommended in CLL patients progressing after chemo-immunotherapy and PI in agreement with current guidelines.
Unfavorable risk chemo-immunotherapy resistant CLL patients that are responsive to PI should continue with the PI or may be offered alloBMT in select circumstances. While there is some agreement regarding proceeding with alloBMT after patients have achieved at least a partial treatment response, it is unclear if depth of response before alloBMT affects survival. A minority of patients have a matched sibling donor (MSD), and thus remaining patients rely on matched unrelated donors (MUDs) or HLA haploidentical donors. Recently, the number of patients undergoing haploidentical alloBMT has increased substantially, with the advent of new graft-versus-host disease (GVHD) prophylaxis strategies such as post-transplant cyclophosphamide (PTCy) that reduce the risk of GVHD complications.
Subsequently, the Dana-Farber group reported that reduced intensity conditioning regimen had superior 5-year OS of 63% compared to 49% with myeloablative conditioning regimens. To date, there is only one report of haploidentical transplant in 117 CLL patients with 5-year OS of 38% and PFS of 31%. 18 Although the haploidentical alloBMT results appear to be substantially lower than HLA matched alloBMT reports, only 38% of the haploidentical alloBMT patients received PTCy GVHD prophylaxis. Therefore the outcome of haploidentical transplant with PTCy in CLL remains unclear. Here we report the outcomes of 64 consecutive CLL patients who underwent non-myeloablative (NMA) haploidentical alloBMT with PTCy GVHD prophylaxis at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins Hospital (JHH).
After JHH institutional review board approval, we queried the SKCCC transplantation database for CLL patients who received haploidentical alloBMT with PTCy GVHD prophylaxis between January 1, 2005 and August 30, 2018. Medical records including clinical notes and pathology, radiology, and laboratory reports were reviewed; data was locked on March 2019. Cytogenetic studies were available for 62 patients (96.8%) and IGHV mutation status was available for 47 patients (73.4%). As per National Comprehensive Cancer Network guidelines: 17p deletion, 11q deletion, complex karyotype (≥3 chromosomal abnormality) or unmutated IGHV were considered unfavorable prognostic features. Pre-alloBMT remission status was assessed according to iwCLL guideline.19 All patients underwent pre-alloBMT bone marrow biopsy. The alloBMT treatment decision was dependent on the treating physician and generally based on presence of unfavorable features, aggressive disease course, and patient’s preference and candidacy for alloBMT. As discussed below, after 2013, patients with greater than 20% CLL marrow cellularity did not meet institutional standards for NMA alloBMT.
All patients received a NMA regimen consisting of fludarabine, cyclophosphamide, and 200cGy total body irradiation (TBI) as described previously. 20 Before 2013, all patients received unmanipulated bone marrow. Because of high rate of graft failure, after 2013 a few patients received G-CSF stimulated marrow and more recently all received G-CSF-mobilized peripheral blood allografts. On days +3 and +4, patients received PTCy (intravenous 50 mg/kg/day). Patients received additional GVHD prophylaxis with mycophenolate mofetil between days +5 and +35, and tacrolimus or sirolimus between days +5 and +180. Development of GVHD in patients led to additional treatment per institutional guidelines as previously described. Our review included patients undergoing alloBMT as standard of care and as part of alloBMT research protocols. OS was time from alloBMT to death from any cause or censoring at the last follow up date.
PFS was time from alloBMT to CLL relapse/progression or death from any cause or censoring at the last follow up date for relapse-free patients. NRM was defined as death from causes not related to CLL relapse. NRM was a competing event when estimating the cumulative incidence (CuI) of relapse and vice versa. For CuI of GVHD, graft failure was a competing event. Death without chronic (c) GVHD was an additional competing event when estimating the CuI of cGVHD. Neutrophil and platelet recovery time was the interval between allograft infusion and first of 3 consecutive days with more than 500 neutrophils/µl or first of 3 consecutive days with more than 20,000 platelets/µl respectively.
Patients were classified as donor T cell engrafted if ≥5% donor cells were detected in peripheral blood CD3+ compartment after day +60 or beyond. Engraftment failure was defined as <5% donor chimerism at any point beyond day +60 in the CD3+ peripheral blood compartment. In T cell engrafted patients, full engraftment was defined by ≥95% donor T cells, while ≥5%-94% donor T cells were considered mixed chimeric. Modified Keystone criteria and National Institutes of Health Consensus Criteria was used to diagnose and score acute (a) GVHD and cGVHD.
The primary endpoint for this study was OS. Patient characteristics and clinical variables were summarized via descriptive statistics. Kaplan-Meier estimators were reported for OS and PFS outcomes. Univariate Cox proportional hazard models were applied for testing the associations
between patient characteristics and OS and PFS outcomes. In addition, we constructed timevarying covariates based on GVHD(t) status to assess the associations between outcomes (OS/PFS) and occurrence of GVHD. The cumulative incidences of relapse, NRM, and GVHD were reported, and Fine and Gray’s regression model25 was applied for univariate analysis in these outcomes. Results from univariate analyses within the lower risk mortality group were reported as exploratory findings. All analyses were carried out using the statistical software R version 3.6.0 (with packages: “survival” and “cmprsk”, R Foundation for Statistical Computing, Vienna, Austria). All reported p-values were two sided. P-values less than 0.05 were considered as statistically significant.
Patient and AlloBMT Characteristics
Between January 2005 and August 2018, 64 consecutive CLL patients underwent haploidentical alloBMT at SKCCC (Table 1). The median age was 59 (range 26 to 74) years. Four patients (6.2%) with Richter’s transformation received alloBMT after first line treatment. Twenty patients (31.2%) underwent alloBMT after second line and 40 patients (62.5%) received alloBMT after three or more lines of treatment for relapsed and/or refractory disease. Chemoimmunotherapy regimens included rituximab single agent (18 patients, 28.1%); alemtuzumab (14 patients 21.8%); bendamustine and rituximab (BR) (24 patients, 37.5%); fludarabine, cyclophosphamide and rituximab (FCR) (25 patients, 39%); rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) (11 patients, 17.1%); and rituximab, ifosfamide, carboplatin and etoposide (R-ICE) (4 patients, 6.2%). Ibrutinib (22 patients, 34.3%) was the most common PI used, followed by venetoclax (12 patients, 18.7%) and idelalisib (3 patients, 4.6%).
Cytogenetic studies were available for 62 patients (96.8%) and IGHV mutation status was available for 47 patients (73.4%). Fifty-six patients (87.5%) had unfavorable prognostic features defined by presence of either del (17p), del (11q), a complex karyotype, or unmutated IGHV sequence. Pre-alloBMT, majority of patients were treatment responsive including 16 patients (25%) in complete remission and 44 patients (68.7%) in partial remission,and rest 4 patients (6.2%) had stable disease. The alloBMT characteristics are listed on Table 2.Female donors served as the allograft source for 17 male patients. Thirty-three patients (51.5%) received bone marrow allografts, 4 patients (6.2%) from G-CSF mobilized bone marrow, and the remaining 27 patients (42.2%) from peripheral blood. The median CD34+ and CD3+ bone marrow allograft doses was 4.8 x 106 cells/kg body weight and 4.1 x 107 cells/kg body weight respectively. The median CD34+ and CD3+ peripheral blood allograft doses was 9.7 x 106 cells/kg body weight and 31.3 x 107 cells/kg body weight respectively
However the 6 patients did have less responsive disease as reflected by their elevated marrow CLL (≥20%) involvement and higher percentage of partial remission and stable disease. While it is generally accepted that CLL patients should undergo alloBMT while patients are treatment responsive, 6 the response threshold that allows engraftment has not be well defined. Our data suggests that CLL marrow involvement of less than 20% is permissive for engraftment in NMA haploidentical alloBMT and provides long term disease-free survival. Unfavorable cytogenetics or IGHV mutation status showed no statistically significant increased risk of post-alloBMT disease progression or reduced survival in patients with < 20% marrow CLL involvement.
While the study was underpowered to exclude impact of unfavorable cytogenetics on post-alloBMT survival, the present results underscore that such high risk features should not be viewed as alloBMT contraindication. Our finding is reminiscent of CLL3X trial15, 16 which showed no survival difference in del (17p) or del (11q) CLL patients and also in multiple myeloma42, 43 where high risk cytogenetics did not affect post-alloBMT survival. Because of the high graft failure rate in our CLL patients before 2013, we switched to peripheral blood allografts for our CLL patients. Unfortunately, we have no data on the use of mobilized peripheral blood for patients with >20% CLL marrow involvement, since we now exclude these patients. However, In patients with <20% CLL marrow involvement, mobilized peripheral blood as compared to marrow as an allograft source did not appear to impact engraftment or survival but was associated increased risk of aGVHD.
This is also consistent with the large study comparing peripheral blood and bone marrow as stem source in haploidentical transplant with PTCy.40 CLL treatment options have improved both in front line1 and the relapsed setting,4, 5 likely reducing the need for alloBMT in this disease. As a result, the role of alloBMT in CLL treatment paradigm is becoming less clear, and more and more is being relegated to patients with disease refractory to multiple agents including PI agents such as ibrutinib or venetoclax. However a significant percentage of relapsed/ refractory CLL patients experience disease progression while on PI46-48 and alloBMT remains one of the few treatment options in this setting. We observed no survival difference between patients receiving pre-alloBMT chemo-immunotherapy or PI drugs including single agent ibrutinib or a combination of ibrutinib, venetoclax and idelalisib. This suggests that the pre-alloBMT response depth and not the pre-alloBMT treatment regimen affect survival.
The majority of our patients had unfavorable risk factors, and collectively our data shows that haploidentical alloBMT with PTCy in CLL with < 20% marrow involvement is a safe treatment option with low risks of serious GVHD and other toxicities. Our study limitations include its retrospective nature and lower statistical power due to limited number of events. We observed disease progression in more than half of our patients with < 20% marrow CLL involvement at 4 years, and similar disease progression was observed by the EBMT CLL allotransplant study14 and the German GCLLSG CLL3X report. Post-BMT maintenance therapy to decrease relapse has been established for oral tyrosine kinase inhibition in Philadelphia chromosome positive acute lymphocytic leukemia. It remains to be seen if post- alloBMT BTK, PI3K, or BCL2 inhibition by PI drugs will improve disease progression and
survival, and we are currently testing such strategies prospectively.
Author: Suman Paul MBBS, PhD , Hua-Ling Tsai MS , Patrick Lowery , Ephraim J. Fuchs MD , Leo Luznik MD , Javier Bolanos-Meade MD , Lode J. Swinnen MBChB, MD, MS , ˜ Satish Shanbhag MBBS, MPH , Nina Wagner-Johnston MD , Ravi Varadhan PhD , Richard F. Ambinder MD , Richard J. Jones MD , Douglas E. Gladstone MD