Post-transplant cyclophosphamide at 80mg/kg with low dose post-engraftment anti-thymocyte globulin in haploidentical transplantation with myeloablative conditioning

doi:10.21203/rs.3.rs-3737986/v1

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Post-transplant cyclophosphamide at 80mg/kg with low dose post-engraftment anti-thymocyte globulin in haploidentical transplantation with myeloablative conditioning

https://doi.org/10.21203/rs.3.rs-3737986/v1

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published 10 Apr, 2024

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While post-transplant cyclophosphamide (PTCy) is commonly used as graft-versus-host disease (GvHD) prophylaxis in haploidentical stem cell transplantation (haplo-HSCT), the dose remains a matter of debate due to side effect concerns. Standard dose PTCy associated with tacrolimus and post-engraftment anti-thymocyte globulin (ATG) was used as the reference GvHD prophylaxis in our center and had demonstrated encouraging results. Though PTCy 80 mg/kg was shown to be feasible in patients in reduced intensity conditioning, whether it exerts equivalent GvHD prophylactic efficacy in myeloablative conditioning (MAC) setting has not been confirmed. Here, we retrospectively analyzed the efficacy and safety of PTCy 80mg/kg combined with tacrolimus and post-engraftment ATG as GvHD prophylaxis in patients aged more than 55 years or with cardiac antecedents or HCT-CI score > 2 undergoing haplo-HSCT with MAC. The cumulative incidence of grade III-IV aGvHD at day 100 and moderate-to-severe cGvHD at 1 year was 4.8%±3.4% and 19.9%±7.0%, respectively. When compared with patients receiving the reference regimen, patients from the PTCy 80mg/kg group had similar incidence of GvHDs and survival as their younger counterparts. Thus, PTCy 80 mg/kg seems to be feasible for patients treated with MAC conditioning regimens in haplo-HSCT, inviting further investigation notably in frail patients.

post-transplant cyclophosphamide

post-engraftment ATG

GvHD

PBSCT

Post-transplant cyclophosphamide (PTCy) is a commonly used strategy for graft-versus-host-disease (GvHD) prophylaxis in haploidentical allogeneic stem cell transplantation (haplo-HSCT)¹. PTCy successfully lowers the incidence of life-threatening GvHD to a level comparable to that after transplants with matched sibling donors, setting the stage for widespread use of haplo-HSCT. Because of its efficacy in preventing GvHD, PTCy has been applied in other allogenic HSCT (allo-HSCT) settings, such as transplants with mismatched unrelated, matched unrelated, or matched sibling donor ^{2, 3}.

One of the major concerns of PTCy is its related toxicities, such as cardiac toxicity and hemorrhagic cystitis (HC), which are associated with higher non-relapse mortality (NRM)⁴ and post-transplant morbidity. The cumulative incidence of early cardiac events post-transplantation varies from 7.4–19% in previous studies, while the incidence of HC varies from 5.4–62% according to the literature^4–7. Although hyperhydration is an effective preventative strategy for HC, it may also lead to complications like fluid overload, which can challenge heart function and aggravate cardiac toxicity, especially among patients of advanced age.

Efforts have been made to decrease the dose of PTCy to limit its toxicities while maintaining efficacy in GvHD prophylaxis. PTCy at doses of 70 mg/kg and 80 mg/kg exerted a comparable GvHD prophylactic effect to standard-dose PTCy in several studies from European groups, mainly among older patients receiving reduced-intensity conditioning (RIC)^{8, 9}. These studies also demonstrated faster engraftment and reductions of infectious and cardiac events in the reduced-dose group. Moreover, superior GvHD and relapse-free survival (GRFS) at 2 years was observed in one study⁸.

To our best knowledge, the efficacy of reduced-dose PTCy has not been specifically evaluated among patients receiving myeloablative conditioning (MAC) regimens. Here, we retrospectively evaluated the efficacy and safety of reduced-dose PTCy among frail patients in a specific GvHD prophylaxis strategy, whereby PTCy is combined with tacrolimus and low-dose post-engraftment anti-thymocyte globulin (ATG) following haploidentical peripheral blood stem cell transplantation.

Patients:

A total of 122 consecutive adult patients enrolled in two prospective clinical trials for acute myeloid leukemia (AML) or myelodysplasia syndrome (MDS) (NCT 04269811 and 03882203) from December 2019 to February 2023 were included in this study. MAC regimens were given according to the trial protocols (Suppl. Table 1). The intensity of the conditioning regimen was classified according to Transplant Conditioning Intensity (TCI)¹⁰. All patients received unmanipulated peripheral blood stem cells from haploidentical donors. Their GvHD prophylaxis consisted of PTCy on days 3 and 4, tacrolimus at a dose of 0.05 mg/kg/d from day 5 onward, and ATG at a dose of 2.5 mg/kg 48–72 h after neutrophil engraftment. At first, all patients received PTCy at a dose of 50 mg/kg on days 3 and 4. From February 2021, patients aged more than 55 years or with clinically significant cardiac antecedents or an HCT-CI score greater than 2 received PTCy at a dose of 40 mg/kg on days 3 and 4. No steroid nor anti-interleukin 6 were administered if haplo-CRS-like symptoms occured¹¹. These studies were approved by the Human Ethics Committee of Rui Jin Hospital and conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all subjects.

Data collection

Electronic medical documents of enrolled patients were reviewed for information on cyclophosphamide-related toxicities, viral infections, and immune reconstitution. In our study, the cyclophosphamide-related toxicities were defined as follows: 1) cardiac toxicity was defined as cardiac failure, arrythmia necessitating the use of a vasopressor, acute pulmonary edema, cardiac ischemia, and pericardial effusion; 2) fluid overload is defined as a gain of body weight more than 5% of baseline, with the presence of pleural effusion or ascites; 3) hemorrhagic cystitis with a severity no less than macroscopic hematuria was counted. Viral infection was diagnosed based on viral load detected by PCR and clinical symptoms. Clinically significant cytomegalovirus reactivation (csCMV reactivation) was defined as CMV reactivation necessitating antiviral treatment. Post-transplant lymphoproliferative disease (PTLD) was diagnosed based on pathological examination. Data for transplantation outcomes, such as the date of engraftment, occurrence and grading of aGvHD or cGvHD, relapse of disease, graft failure, non-relapse mortality (NRM), and death were all retrieved from the patients’ database.

Statistics

Patient characteristics between groups were evaluated using Fisher’s exact test for categorical variables and t tests for continuous measures. Differences in time to events between patient groups were estimated with Cox proportional hazards models. The cumulative incidence of cGvHD was calculated as the time from transplant to diagnosis of cGvHD (event), relapse (competing event), primary graft failure (competing event), death not due to cGvHD (competing event), or last follow-up if still alive (censored). The cumulative incidence of NRM was calculated as the time from transplant to death not related with relapse (event), death related with relapse (competing event), or last follow-up if still alive (censored). GRFS was calculated from day of transplant to the diagnosis of grade III–IV aGvHD, moderate-to-severe cGvHD, relapse, graft failure, death of any cause, or last follow-up. Comparisons of engraftment, GvHD, NRM, and relapse between patient groups were estimated with cumulative incidence estimates and Cox proportional hazards by Fine and Gray’s method. Univariate and multivariate analyses were performed to identify factors associated with NRM and cumulative incidence of relapse (CIR). Factors with a p < 0.1 in univariate analysis were included in the multivariate analysis, which was performed with Cox’s proportional hazards regression model. Statistical analyses such as parametric, non-parametric, and chi square tests were performed using GraphPad Prism (GraphPad Software, San Diego, California, USA). Statistical analyses for survival and cumulative incidence of events were performed by R 4.0.4 software downloaded from https://www.r-project.org/.

Patient characteristics

The characteristics of 46 patients receiving PTCy at a dose of 80mg/kg are summarized in Table 1. The median age was 57 (14–66) years old. Three patients were non-evaluable by DRI because of lack of Karyotype results at diagnosis. One patient was diagnosed with primary graft failure and underwent a second allo-HSCT with matched unrelated donor successfully. Another patient died before engraftment. The cumulative incidence of neutrophil engraftment at day 30 was 96.7% and the cumulative incidence of platelet engraftment at day 100 was 97%.

Transplant outcomes after reduced dose PTCy

The median follow-up of patients receiving reduced dose PTCy was 469 (20-1023) days. The cumulative incidence of aGvHD and grade II-IV aGvHD at day 100 was 26.7%±6.7% and 14.3%±5.5%, respectively (Fig. 1). The cumulative incidence of grade III-IV aGvHD at day 100 was 4.8%±3.4%. The cumulative incidence of cGvHD and moderate-to-severe cGvHD at 1 year was 46.2%±7.6% and 19.9%±7.0%, respectively (Fig. 1). The CIR at 1 year was 2.6%±2.6%. The cumulative incidence of NRM at 1 year was 17.9%±5.8% (Fig. 1). The causes of death included 3 cases of cerebral vascular events, 2 cases of infection, 2 case of cardiac toxicity, 1 case of secondary graft failure. No patient died from uncontrolled GvHD.

The overall survival (OS) and disease-free survival (DFS) at 1 year was 81.7% (71-94.2%) and 79.2% (67.9–92.4%), respectively (Fig. 2). The GRFS at 1 year was 62.7% (50.1–78.5%).

Horizontal comparison with standard dose PTCy

To evaluate the efficacy and safety of reduced dose PTCy in a horizontal way, we compared the transplant outcomes between the 46 patients receiving PTCy 80mg/kg and another 76 patients enrolled in the same prospective clinical trials receiving PTCy 100mg/kg. The baseline characteristics were compared and summarized in Table 1. The major difference lay in the median age, distribution of HCT-CI score, the donor type and the median follow-up duration. These differences are associated with the criteria for administering reduced-dose PTCy. Differences in donor type mainly occurred because of the higher age of patients in the PTCy 80 mg/kg group. Patients in the PTCy 80 mg/kg group were infused with higher amounts of mononuclear cells than those in the PTCY 100 mg/kg group (p = 0.03).

Impact of PTCy dose on transplant outcomes

Two patients from the PTCy 100mg/kg were diagnosed with primary graft failure and one of them underwent a second allo-HSCT successfully. Cumulative incidences of neutrophil engraftment at day 30 (p = 0.44) and platelet engraftment at day 80 (p = 0.58) were similar between patients receiving 100 mg/kg and 80 mg/kg PTCy. When compared with PTCy 100mg/kg, reducing the dose of PTCy to 80 mg/kg did not increase the incidence of grade II–IV aGvHD (p = 0.47) or grade III–IV aGvHD (p = 0.26) as is shown in supplementary Fig. 1. Incidences of cGvHD (p = 0.11) and moderate to severe cGvHD (p = 0.24) were comparable between the two groups (Fig. 3).

The cumulative incidence of NRM was significantly higher in the PTCy 80 mg/kg group (p = 0.03, 17.9%±5.8% vs 5.3%±2.6% at 1 year in PTCy 100mg/kg and PTCy 80mg/kg group respectively, as is shown in Fig. 3) but the cumulative incidence of relapse was similar between groups (p = 0.09) as is shown in supplementary Fig. 1. No significant difference in OS (p = 0.1) or DFS (p = 0.8) was observed between groups. GRFS was not significantly different between groups (p = 0.2) (Fig. 4). Moreover, the proportion of patients free of immunosuppressive agents was comparable between the two groups (Suppl. Figure 2).

As NRM was significantly higher in PTCy 80mg/kg group, we next performed univariate and multivariate analysis for NRM. Age of patient, TCI, DRI, sequential conditioning regimen, HCT-CI score and PTCy dose were included in the univariate analysis, among which higher DRI, higher HCT-CI score and reduced PTCy dose were correlated with increased risk of NRM. In multivariate analysis, higher DRI and higher HCT-CI score remained independent risk factor for higher risk of NRM (Table 2). Meanwhile, as patients from reduce PTCy group had a trend to have lower risk of CIR, we also performed univariate and multivariate analysis for CIR. Though DRI, TCI and disease status before transplant were significantly corelated with the risk of CIR in univariate analysis, none of them turned out to be independent risk factor of CIR.

Impact of PTCy dose on toxicities and immune reconstitution

In this report, the overall incidence of toxicities was low, partly associated with the restricted definition of toxicities in our study. The incidences were similar in 100 mg/kg and 80 mg/kg PTCy groups (Table 3). Two patients in each group died from PTCy-associated toxicity.

The recovery of absolute lymphocyte counts within the first-year post-transplant was comparable between the two groups. Lymphocyte subpopulation analysis showed higher absolute CD8 + T lymphocyte counts in the PTCy 80 mg/kg group at 9 months (p = 0.005) and 12 months (p = 0.02) post-transplant; whereas, CD4 + T lymphocyte recovery, NK cell recovery, and B cell recovery were not significantly different between groups (Suppl. Figure 2).

Impact of PTCy dose on viral reactivation after allo-HSCT

The incidences of overall CMV reactivation were 65.3% and 59.1% of patients in the 100 mg/kg and 80 mg/kg PTCy groups, respectively (p = 0.56). Incidences of csCMV reactivation were 54.2% and 43.2%, respectively (p = 0.34). Furthermore, the incidence of CMV disease demonstrated a decreasing trend in the PTCy 80 mg/kg group (0% in PTCy 80 mg/kg vs. 8.3% in PTCy 100 mg/kg, p = 0.08). Epstein-Barr virus reactivation was similar between groups. One patient in the PTCy 80 mg/kg group was diagnosed with PTLD and responded well to rituximab. Overall, the incidence of any viral infection was low and similar between the two groups (Table 4).

In our study, PTCy at a standard or reduced dose was used in combination with tacrolimus and low-dose post-engraftment ATG as GvHD prophylaxis for patients with AML and MDS undergoing first allo-HSCT from a haploidentical donor. Various combinations of PTCy and ATG have been explored by several groups. Most combinations consisted of pre-transplant ATG and PTCy at varying doses, showing low rates of grade III–IV aGvHD and cGvHD along with amelioration of GRFS^{9, 12–15}. The most common cause of death was infection in these regimens¹². More recently, post-transplant ATG with PTCy has emerged as a feasible combination. One study exploring the efficacy of post-transplant low-dose ATG on day 8 added to 80-mg/kg PTCy observed an overt reduction of GvHD and superior GRFS compared with the findings with 10-mg/kg ATG alone¹⁶. However, an Italian study adding a single dose of 5-mg/kg anti T-lymphocyte globulin (ATLG) on day 5 to standard dose PTCy delayed platelet engraftment ¹⁷. Survival outcomes were comparable between groups and the addition of ATLG significantly reduced the incidence of cGvHD without impacting the incidence of aGvHD. Immune reconstitution was impacted without increasing the risk of relapse or infection¹⁷. Thus, the combination of PTCy and ATG/ATLG in various patterns is demonstrated to be a safe and promising approach for patients with hematological malignancies undergoing allo-HSCT.

To our knowledge, our group is the first to apply post-engraftment ATG in combination with PTCy. Our adjustment takes full advantage of PTCy in purging alloreactive lymphocytes and of ATG to further diminish lymphocytes escaped from PTCy at engraftment.

Apart from the use of post-engraftment ATG, another major difference between our study and previously published studies comparing standard and lower doses of PTCy lies in the intensity of the conditioning regimen, which is a risk factor for GvHD. Patients treated with MAC display a higher risk of GvHD than those treated with RIC. Although European groups have demonstrated parallel efficacy and safety of PTCy 80 mg/kg among geriatric patients receiving RIC regimens^{8, 9}, this dose of PTCy has not been specifically evaluated among patients receiving MAC regimens. Attempts to reduce PTCy doses for patients of advanced age and higher HCT-CI scores are driven by their fragility to chemotherapy and higher risk of developing treatment-related comorbidities and mortality. Based on the encouraging outcomes of low GvHD with standard-dose PTCy and post-engraftment ATG from our former study¹⁸, here we treated patients older than 55 years old or with a HCT-CI score ≥ 3 or with prior cardiac history with reduced dose PTCy at 80mg/kg and found similar incidence of GvHD and comparable post-transplant survival compared with standard dose PTCy. Though reduced dose PTCy was corelated with increased risk of NRM in univariate analysis, the result of multivariate analysis brought evidence that this risk of mortality was linked with comorbidity and disease related risk instead of the dose of PTCy. Indeed, our group of frail patients whom we evaluated to be in need of reduced dose PTCy still underwent a higher rate of NRM; however, our study showed that the combination of reduced PTCy, tacrolimus and post-engraftment ATG allowed them to obtain comparable overall survival and quality of life as their younger and fitter counterpart.

Our cohort had limited capacity to fully evaluate the impact of reduced-dose PTCy on the incidence of toxicities (e.g., cardiac events or fluid overload) due to the limited number of these events, which was basically the aim of using lower doses of cyclophosphamide. In addition, one can say that the major limitation of our study lies in the demographic difference between the two groups, which is linked with the design of this retrospective study. It is correct, however real-life treatment strategy must consider the reality of the population to be successful. Our study suggests that a reduced dose of PTCy associated with post-engraftment ATG and tacrolimus for haplo-HSCT after MAC is not associated with higher incidences of graft failure or GvHDs. However, to know if this approach conducts to better results, notably in older patients, can only been assessed in a prospective study.

Author contributions

LiniW and GX performed the transplants in patients in the prospective clinical trials, collected the patient data, and wrote the manuscript. LiniW, WG, and MW performed the statistical analysis. LW and JJ supervised the prospective clinical trials and followed-up with the patients. DB and JH designed and supervised the study, and wrote the manuscript. All authors contributed to the article and approved the submitted version.

Acknowledgments

We thank all clinical fellows and the nursing staff of the Blood and Marrow Transplantation Center, Department of Hematology, Ruijin Hospital.

Competing Interests:

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data Availability Statement:

The datasets generated and analyzed during the current study are available from the corresponding author with the following contact [email protected].

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Tables are available in the Supplementary Files section.

The authors have declared there is NO conflict of interest to disclose.

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You are reading this latest preprint version

Post-transplant cyclophosphamide at 80mg/kg with low dose post-engraftment anti-thymocyte globulin in haploidentical transplantation with myeloablative conditioning

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Patients:

Data collection

Statistics

Results

Patient characteristics

Transplant outcomes after reduced dose PTCy

Horizontal comparison with standard dose PTCy

Impact of PTCy dose on transplant outcomes

Impact of PTCy dose on toxicities and immune reconstitution

Impact of PTCy dose on viral reactivation after allo-HSCT

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1