Clofarabine and Total Body Irradiation (TBI) as Conditioning Regimen for Allogeneic Stem Cell Transplantation in High-Risk Acute Leukemia Patients.

Abstract

Background: Clofarabine (Clo) is an immunosuppressive purine analog that may have better anti-leukemic activity than fludarabine (Flu) in the conditioning regimen for allogeneic stem cell transplant (allo-SCT) for acute leukemia patients. The addition of total body irradiation (TBI) to conditioning regimens has been widely investigated. However, the use of single agent Clo in combination with intermediate doses of TBI ranging from 4-8 Gy has not been studied yet.

Objective: This study aims to identify the outcome of patients with high-risk hematological malignancies who underwent allo-SCT from different donor types and received Clo and TBI (4-8 Gy) as a conditioning regimen.

Methods: This is a double center, observational, retrospective study of patients with high-risk hematological malignancies diagnosed from 2012 to 2021, treated at the American University of Beirut Medical Center in Beirut (AUBMC), Lebanon, and Saint-Antoine Hospital (SA) in Paris, France. Data regarding patient baseline characteristics, disease-related factors, and transplant outcomes including graft-versus-host disease (GVHD), Non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), were collected.

Results: We identified 24 high-risk patients with a median age at transplant of 37 years (range 22-78). Of these, 15 patients (63%) were males, 8 patients (33%) had acute myeloid leukemia (AML), 3 patients (13%) had myelodysplastic syndrome (MDS), and 12 patients (50%) had acute lymphoblastic leukemia (ALL), and 1 patient had B-lymphoblastic lymphoma (B-ALL) (4%). At the time of the transplant, only 15 patients (63%) were in complete remission (CR). Nine patients (38%) received transplants from a matched related donor(MRD), 9 patients (38%) from a haploidentical related donor(haplo), 4 patients (17%) from a matched unrelated donor(MUD), and 2 patients (8%) from an unrelated cord blood donor (UCB). All patients received Clo. For TBI, 21 patients (88%) received a total dose of 4 Gy, and 3 (12%) received 8 Gy. Sixteen patients (67%) received anti-thymocyte globulin(ATG). After a median follow-up of 40 months, the cumulative incidences of grade II-III acute GVHD, grade IV acute GVHD, and chronic GVHD were 50%, 4%, and 8%, respectively. NRM at 100 days, and 1 year after transplant was 4% and 25%, respectively. 17% of the patients had a relapse or progression of the disease by the end of the study. The 2-year PFS and OS were 50% and 56%, respectively. The median PFS and OS were not reached.

Conclusions: Clo/TBI (4-8 Gy) as a conditioning regimen for allo-SCT in high-risk patients confers disease control with an acceptable toxicity profile.

Introduction

Allo-SCT remains the only curative option for patients with high-risk hematologic malignancies or acute leukemia[1]. The nonmyeloablative (NMA) conditioning regimen is the least intense of the conditioning therapies and the most tolerated[2]. Reduced-intensity conditioning (RIC) regimens emerged around two decades ago with the aim of decreasing the toxicities and morbidities related to allo-SCT. The concept of RIC switched progressively to the concept of reduced-toxicity conditioning (RTC) regimens, which are currently the most used conditioning regimens worldwide. Due to lower NRM associated with RIC and RTC, such regimens allow older patients or those with co-morbidities to be transplanted. The combination of Flu, an intermediate dose of intravenous busulfan, and low dose ATG is among the most popular RIC regimen used in Europe, particularly in France. Other RIC regimens involve other drugs such as a combination of Flu, melphalan, busulfan, and ATG[3-6]. Nevertheless, relapse remains a challenge after such regimens. Therefore, attempts to intensify the RIC regimen without increasing NRM might be an attractive option to obtain better disease control while waiting for the immune graft-versus-leukemia (GVL) effect. Thus, the incorporation of new drugs with greater anti-tumor activity and acceptable toxicity merits further investigation as part of the RTC approach.

Historically, 20% of allo-SCT performed after NMA regimens resulted in graft failure and rejection; the addition of Flu to these regimens decreased the rejection rate to 3%. Flu's efficacy was proven in many studies of allo-SCT and haplo-SCT. However, disease-related mortality remained high[7].

Clofarabine (Clo) is a second-generation purine analog that requires intracellular phosphorylation to be active. Clofarabine triphosphate impedes DNA synthesis and repair by inhibiting ribonucleotide reductase and DNA polymerase. It has been documented that Clo has significant anti-leukemic activity, particularly in relapsed AML and ALL, and the drug is approved by the United States Food and Drug Administration for the treatment of pediatric ALL patients after at least two prior regimens. Hand-foot syndrome and reversible liver function abnormalities are the two main complications of the drug. Clo combines the most favorable pharmacokinetic properties of the first-generation purine analogs, namely Flu and cladribine, with superior anti-leukemic activity, due to increased resistance to deamination and phosphorolysis, conferring better drug stability[8]. Direct induction of apoptosis by activation of caspase-9, and direct interaction with the mitochondrial membrane may also play a role in this superior anti-leukemic effect[9]. Clo is also more active in non-dividing lymphocytic cells, which might give more immunosuppression and decrease engraftment failure[10]. Due to its strong anti-leukemic action and lower organ toxicity compared to Flu, it has been increasingly used in adult patients, not only as an alternative to RIC regimens but also as a RTC alternative to standard myeloablative (MA) regimens.

Thus, one can also exploit the anti-leukemic, immunosuppressive effects and Clo’s favorable toxicity profile in an RTC regimen setting before allo-SCT. Many studies have also been also carried out to evaluate the efficacy of Clo, in place of Flu to tackle the high relapse rate[10-13]. A phase 1 study of Clo 52 mg/m2 with TBI (2 Gy), published in 2017, was performed with 18 pediatric patients with hematologic malignancies in CR and considered to be at high mortality risk from MA conditioning regimens. At one-year post-transplant, the mortality rate due to disease progression was 33%, NRM was 0%, event-free survival (EFS) was 60%, and OS was 71%. It was concluded that Clo/TBI can be used for successful engraftment while maintaining a low rate of NRM in pediatric leukemia patients[10].

Another study retrospectively compared Clo versus the same regimen with Flu (FLAG or FA, retrospectively) in combination with high-dose cytarabine with or without granulocyte colony-stimulating factor (GCSF). The study included 151 patients and showed that treatment with Clo was associated with higher CR rates and longer survival even after accounting for other variables, especially in patients with unfavorable genetics or a short duration of first CR[11] . Another retrospective study of 355 AML/MDS patients who were allo-transplanted between 2009 and 2014 and received either Clo/busulfan x 2 days (CloB2ATG2) or a Flu/busulfan x 2 days with ATG x 2 days (FB2ATG2) showed that FB2ATG2 was associated with lower OS (hazard ratio [HR]=2.14, P=0.04) and higher relapse risk (HR=2.17, P=0.04)[12].

Another retrospective study in France, of 36 adult patients with myeloid malignancies, treated between 2014 and 2017 with Haplo-SCT, treated the patients with the Baltimore RIC regimen and high-dose post-transplant cyclophosphamide (PTCy). However, they replaced Flu with Clo, bone marrow (BM) with peripheral blood stem cells (PBSC), and tacrolimus with cyclosporine A (Clo-Baltimore). The Clo-Baltimore regimen showed encouraging results for patients regardless of disease activity at transplant. All the patients engrafted except for one. The rates of acute GVHD grade II-IV and chronic GVHD were 49% and 21% respectively. The two-year disease-free survival was 52% and OS was 66%. The Clo-Baltimore outcomes were superior to the classical Baltimore outcomes with EFS of 26%, and OS of 37%[13].

With all of these studies showing the efficacy of Clo, this paper is mainly focused on exploring the outcomes of using Clo together with TBI (4-8 Gy) as conditioning therapy before allo-SCT.

Materials And Methods

This is a retrospective, double-center, observational study conducted at Naef K. Basile Cancer Institute (NKBCI) at the American University of Beirut Medical Center (AUBMC), Beirut, Lebanon and the Department of Hematology, Saint Antoine Hospital (SAH), Paris, France. Both centers being part of the same collaborative group, follow the same transplantation protocols and provide identical supportive care. It involves all adult patients aged ≥18 years who received an allogenic BM transplantation and had Clo/TBI (4-8Gy) as an induction therapy pre-transplant at the AUBMC or SAH between September 2012 and October 2021.

We identified 24 patients in total with 13 and 11 identified at the AUBMC and SAH, respectively. We did not divide our patients into groups since our research design was descriptive in nature. Acute GVHD was defined as GVHD that had occurred within the first 100 days post Haplo-SCT and chronic GVHD was defined as GVHD that had occurred after 100 days from transplant. Acute GVHD was diagnosed and graded according to the revised Glucksberg criteria[14], and chronic GVHD was diagnosed and graded according to the Seattle standard criteria[15]. Time to neutrophil recovery was defined as the first of three consecutive days in which the absolute neutrophil count exceeded 0.5 × 10⁹/L and platelet recovery as the first of five consecutive days with a platelet count above 50 × 10⁹/L without the need for platelet transfusion.

Transplantation procedure

Conditioning regimens consisted of Clo 30 mg/m² on days -5 to -3 if administered with TBI 8 Gy and from days -4 to -2 if administered with TBI 4 Gy. As for TBI, patients received a total of 4 Gy divided into 2 doses of 2 Gy on day -1, or a total of 8 Gy divided into 2 doses daily on days -2 and -1. ATG was given at a dose of 2.5 mg/kg/day with the last dose of Clo (Day -3 or -2).

All patients received mycophenolate mofetil (MMF) administered at a 15-mg/kg dose 2 times per day beginning on day +6 post Haplo-SCT (maximum dose, 1g orally, 2 times per day) and stopped between day +28 to +35 if there was no severe GVHD. All patients received cyclosporine A 1.5 mg/kg every 12 hours starting on day -3. In the case of a Haplo donor, patients received PTCy 15 mg/kg on days +3 and +5.

All the patient-, donor-, and transplantation-related characteristics are summarized in Table 1.

Supportive Care

Prophylaxis of hepatic veno-occlusive disease (VOD) was provided with orally applied ursodeoxycholic acid. Patients at high risk of VOD according to the European Society for Blood and Marrow Transplantation (EBMT) criteria, received defibrotide[16, 17].

Antimicrobial prophylaxis consisted of valacyclovir or acyclovir, administered at the start of the conditioning regimen. After engraftment, patients received trimethoprim-sulfamethoxazole. Primary antifungal prophylaxis with voriconazole was administered at AUBMC and fluconazole at SAH from day -4 until the end of the immunosuppression[18]. Patients were monitored weekly by real-time polymerase chain reaction (PCR) for cytomegalovirus (CMV) and Epstein-Barr virus (EBV), until day +100. Monitoring of human herpesvirus 6 (HHV6) and BK virus in blood and urine was done according to clinical signs only. Additional supportive care was provided according to our institutional guidelines, including prophylactic antibiotics.

Statistical Analysis:

Patients’ characteristics were summarized using descriptive statistics, including the median (range) for continuous variables and frequency (percentage) for categorical variables. Multivariate analysis for acute GVHD, chronic GVHD, NRM, PFS, and OS, was performed using a binary logistic regression using a backward stepwise elimination process in which only significant variables that best explained the data were kept in the model.

The survival rates were estimated by the Kaplan-Meier method and compared by a log-rank test. All P values were 2-sided, with a significance level of .05. All statistical analyses were performed using IBM SPSS Statistics, version 27.

Results

The patients included in this study were treated in one of two centers, AUBMC in Lebanon (n=13) and SAH in France (n=11) between 2012 and 2021. All patients were treated with Clo/TBI (4-8 Gy) for hematologic malignancies such as AML (33%), MDS (13%), ALL (50%), and B-ALL (4%). 63% of the patients were male. The median age at transplant was 37 years (range 22-78). Four patients (17%) were aged ≥60 years at the time of the transplant. 46 % of the patients had an EBMT risk score of 0 at the time of transplant and 45% had an EBMT score of ≥2. With respect to the DRI score, 42% had an intermediate DRI score and 58% had a high or very high score.

Fifteen (62.5%) of the patients were transplanted in CR and eight (33.5%) were transplanted with persistent or refractory disease. PTCy was used in 33% of the patients. The median follow-up was 40 months (range 1-110).

Nine (38%) of the donors were MRD, nine (38%) were Haplo, four (17%) were MUD, and two (8%) were transplanted from umbilical cord blood (UCB). Nineteen patients (79%) of the patients have never had a transplant at the time of the intervention, while five patients (21%) of the patients had received a second transplant as salvage after an initial relapse post first allo-SCT. GVHD prophylaxis and immunosuppression comprised cyclosporine A (100%) and MMF (96%), respectively.

Sixteen (67%) patients developed acute GVHD and 11 (50%) had grade II-III acute GVHD with only one patient having grade IV acute GVHD. The mean time of onset of acute GVHD after transplant was 57.5 days (range 20-132). At the study end, only two (8%) patients had developed chronic GVHD.

Table 2 shows the outcome results. The global mortality rate was 46% at the end of the follow-up period. The 1-year NRM was 25%. Only four (17 %) patients experienced relapse or progression of the disease by the end of the study, with three patients experiencing this at 2-years. The relapse incidence was 13% at 2 years post-transplant. The GVHD-free, relapse-free survival (GRFS) at 1-year was 25%.

The mortality related to relapse or refractory disease was 21% (n=5). In this study the median PFS and OS were not reached. However, the PFS and OS at 2 years were 50% and 56%, respectively.

Discussion

This study describes the outcomes of 24 adult patients with high-risk acute leukemia receiving a Clo/TBI (4-8 Gy) conditioning regimen before allo-SCT. To our knowledge, it is the first study to look at the use of Clo with intermediate or high dose TBI (4-8 Gy) as a conditioning regimen in this high-risk patient population. Hence, this study may fill a crucial gap in the literature. Our results are very encouraging and show that Clo/TBI (4-8 Gy) is a reasonable conditioning therapy before allo-SCT in leukemia patients given the acceptable disease control and relatively low toxicity profile in comparison to other RIC regimens including flu/TBI. The high-risk population in our study is demonstrated by the DRI score, EBMT score, number of second transplants, and the percentage of patients above 60 years old.

The 2-year relapse rate and OS of 17% and 56%, respectively, compare favorably to the rates observed in other studies using other RIC regimens (19). Most retrospective studies have found that the expected relapse rate is between 35% to 65% and OS rate is between 23 % and 60% at a median follow-up of 24 to 36 months in patients who had RIC conditioning before allo-SCT[19].

In a retrospective large French registry of 1108 younger patients who received RIC (Flu/TBI, Flu/busulfan/ATG) and allo-SCT from MRD or MUD, the OS was 42% after a median follow-up of 21 months[20]. In a Dana-Farber Cancer Institute study on 422 patients who received RIC (Flu/busulfan) before MRD or URD allo-SCT, the relapse rate was reported as 65% and 52%, respectively. The OS was 50% and 56%, respectively, mirroring the results in our study[21]. In another study reported by the CIBTMR on 768 patients of median age 51 years, receiving MRD/URD PBSC transplants with RIC conditioning, the relapse and OS rates were 35% and 40%, respectively[19, 22]. This is very reassuring since our study's relapse and OS rates fall in the range observed with other RIC conditioning regimens.

The adequate OS and low relapse rate discussed suggests that mortality related to relapse or progression might be improved with the use of Clo. In this study, the mortality due to relapse is 21% with a median follow-up of 40 months. A study on the use of Flu/low-dose TBI as an NMA regimen has shown an overall 5-year relapse mortality of 34.5%[19]. This shows that the use of Clo/TBI might decrease the relapse rate (which is the main hindrance to the use of our conditioning regimen) and hence relapse mortality.

Interestingly, the low relapse rate in our study did not come at the expense of increased toxicity such as acute and/or chronic GVHD. Cumulative incidences of grade II-III acute GVHD, grade IV acute GVHD, and chronic GVHD were 50%, 4%, and 8%, respectively.

In the French registry study, the incidence of grade II-IV acute GVHD was 28%[20]. In the CIBTMR study, the incidence of grade II-IV acute GVHD was 41 to 47% depending on the source of the graft[22]. The incidence of chronic GVHD was shown to range from 25% to 45 %[22]. In a prospective phase 3 randomized clinical trial comparing Flu/TBI 2 Gy and TBI 2 Gy on 85 patients with different hematological malignancies, the grade II-IV acute GVHD and chronic GVHD incidence was 46% and 72%, respectively, in the Flu/TBI group[7]. These results show that there might be a slight increase in the risk of acute GVHD with the use of Clo/TBI (4-8 Gy) in comparison to Flu/TBI (2 Gy) and other RIC regimens. The higher rate of acute GVHD might be related to the increased mucositis induced by Clo, which can lead to exposure of donor T-lymphocytes to self-antigens[10]. However, the increase in acute GVHD in our study did not lead to increased NRM, which was 25% (6 patients) at the end of the follow-up period. Three of these died from severe infection and three deaths were secondary to refractory acute GVHD. Interestingly, this NRM is inferior to the rates seen with other MA regimens as expected and comparable to those seen with other RIC regimens[19]. In a review by Storb and Sandmaier, the NRM associated with RIC conditioning falls between 6% and 38% and the NRM in the retrospective CIBTMR study was 35%[22]. The NRM reported in the French registry study was 15% after a shorter median follow-up of only 21 months[20]. The NRM seen in the Dana-Farber Cancer Institute study fell between 6% and 8%[21].

This shows clearly that our Clo/TBI conditioning regimen might be the key to decreasing relapse rates in the future without increasing toxicity and/or mortality. These results and outcomes may be explained by different causes: 1) higher anti-leukemic activity of Clo compared to Flu, 2) higher immunosuppressive potential effect secondary to the anti-lymphocytic activity, increasing the possibility of successful engraftment and the GVL effect.

Conclusion

In summary, the main goal of RIC/RTC regimens is to make allo-SCT possible for elderly patients and younger patients with comorbidities. This is the first study to evaluate a modified form of a new conditioning regimen using Clo with an intermediate/high dose of TBI. Our results demonstrate that our regimen of Clo/TBI is associated with greater GVL activity; it has also proven to be relatively safe with manageable toxicity and could have a practice-changing impact in the future for high-risk acute leukemia patients who are candidates for allo-SCT.

Declarations

Conflict of Interest: All authors declare that they have no conflict of interest.

Ethics approval: 

This study gained international review board approval and ethics committee approval in the AUMBC and SAH. All patients gave informed consent for the collection of their data in this database. Data were collected from chart reviews, and test results were cross-checked using various methods of verification, including matching of several sources of data, on-site verification, and computerized searches for discrepancy errors. 

Acknowledgments: 

The authors thank the nursing staff and all the physicians at our two centers for providing excellent patient care.  

Funding: 

No specific funding was disclosed.

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Tables

Table 1 – Patient, donor, and transplant characteristics 

 *Percentages may not add up to 100% due to rounding

1- CR: Complete remission

2- TBI: Total Body Irradiation

3- acute GVHD: Acute graft-versus-host disease

4- Percentages don’t add up to 100% as many patients had acute GVHD at multiple sites

Other abbreviations needed eg. NRM, MMF, PTCy, MUD, MDS, AML etc

Table 2: Patient treatment outcomes