In this pilot study, the safety and efficacy of PTCY at a reduced dose of 40 mg/kg/day on days + 3/+4 were assessed in recipients of MRD and MUD PBSC alloHSCT. The results revealed low incidences of grade II-IV and grade III-IV acute GVHD, and moderate-severe chronic GVHD (18.2%, 4.5%, and 6.4% respectively), comparable to the standard PTCY dose of 50 mg/kg/day. No cases of grade IV acute GVHD or steroid-refractory disease were observed. Furthermore, none of the patients presented primary graft failure, indicating that PTCY at 40 mg/kg/day is both effective and safe.
In current clinical practice, the standard dose of PTCY at 50 mg/kg/day and its timing have been derived partly from murine MHC-matched skin allografting models and partly from empirical approaches. Recently, Wachsmuth et al investigated the impact of varying doses of PTCY (5, 10, 25, 50 mg/kg/day) and timing (post-transplant days from + 1 to + 8) on its effectiveness in mitigating GVHD severity in a murine MHC-haploidentical alloHSCT model [22, 23]. Overall, their findings suggest that PTCY reaches its maximal efficacy when given on day + 4, and PTCY given on day + 4 alone may be as effective as varied doses on days + 3/+4. Notably, a PTCY dose of 25 mg/kg/day on day + 4 was found to be equivalent to 25 mg/kg/day administered on days + 3/+4 in preventing severe GVHD. This data supports the initiation of clinical trials aimed at exploring PTCY dose de-escalation.
In haploidentical transplantation, several studies have evaluated reduced doses of PTCY, either alone or in combination with ATG. This setting carries a higher risk of GVHD and graft failure compared to MRD or MUD transplant recipients. PTCY doses vary from 40mg/kg/day on days + 3/+4 to 14.5mg/kg/day on the same days, usually in combination with two to four immunosuppressant drugs [24–28]. Overall, the results of these studies show that PTCY dose de-escalation is feasible, allows hematopoietic engraftment and does not increase the risk of GVHD compared to standard doses.
Limited information, summarized in Table 2, is available on the use of reduced doses of PTCY with or without ATG in the setting of HLA-mismatched, MRD, and MUD alloHSCT.
Table 2
Summary of the results of studies using reduced doses of PTCY with/without ATG in the setting of HLA-mismatched, MRD, and MUD alloHSCT.
Author | N | Type of donor | PTCY dose | Other immunosuppressant drugs | II-IV acute GVHD* | III-IV acute GVHD* | All-grade chronic GVHD** | Moderate-severe chronic GVHD** |
Juárez et al. | 22 | MRD, MUD | 40 mg/kg/day + 3/+4 | Tac | 18.2% | 4.5% | 11.4% | 6.4% |
Sun et al. [29] | 51 | MRD, MUD | 50 mg/kg/day + 3 | ATG + CsA + MMF | 6.2% | 0% | 11.5% | NR |
Zu et al. [30] | 53 | MRD MUD | 20 mg/kg/day + 3/+4 | ATG | 24.5% | NR | 14.1% | NR |
Solterman et al. [31] | 22 | 1-antigen MMUD | 40 mg/kg/day + 3/+4 | CsA + MMF/MTX | 15% | NR | 26% | NR |
Zhang et al. [32] | 29 | HLA-identical donors | 3 + 3 design trial DL1: 50 mg/kg/day + 3/+4 DL2: 50 mg/kg/day + 3 and 25 mg/kg/day + 4 DL3: 25 mg/kg/day + 3/+4 | CsA | 28.6% (for 21 patients with DL3) | 0% (1 patient at day + 141) | 37.3% | 16% |
García-Cadenas et al. [33] | 14 | MRD MUD 1-antigen MMUD | 30 mg/kg/day + 3/+4 | Tac | 28.6% | 7% | 36% | 14% |
* Cumulative incidence at day + 100; ** Cumulative incidence at 1-year; NR, Not Reported; DL, dose level. |
In the protocol by Sun et al., the GVHD prophylaxis regimen consisted of a single dose of PTCY 50 mg/kg on day + 3, ATG, CsA and MMF [29]. The incidences of grade II–IV acute GVHD at + 100 days and mild-to-moderate chronic GVHD within 1 year were 6.2% and 11.5%, respectively. The results observed in our study using a simpler GVHD prophylaxis regimen, with PTCY 40 mg/kg/day on days + 3/+4 and Tac instead of four immunosuppressants, were quite similar (4.5% for grade II–IV acute GVHD and 11.4% for all-grade chronic GVHD). In the second study, a comparison was made between PTCY 20 mg/kg on days + 3/+4 with low-dose ATG and a quadruplet ATG-based regimen using ATG, methotrexate, CsA, and MMF in patients undergoing HLA-identical MUD-PBSC transplants [30]. The incidence rates of grade II-IV acute GVHD and chronic GVHD at 2 years were significantly reduced in the low-dose PTCY-ATG cohort (24.5% vs. 47.1%; 14.1% vs. 33.3%), indicating a positive effect of this treatment approach.
Three studies evaluated reduced doses of PTCY without the addition of ATG in recipients of MRD or MUD transplants [31–33]. Solterman et al. conducted a retrospective analysis of PTCY 40 mg/kg/day on days + 3/+4, followed by CsA and MMF, in 22 patients who underwent 1-antigen HLA-mismatched unrelated donor transplant [31]. The authors compared this group with 58 patients who received ATG, CsA, and either methotrexate or MMF. The PTCY group had a significantly lower incidence of acute GVHD grade II-IV (15% vs. 50%), while chronic GVHD was similar (26% vs. 35%). In our study using Tac alone combined with PTCY 40 mg/kg/day, the incidence of acute GVHD grade II-IV was very similar (18.2%). Zhang et al. recently presented the results of a prospective phase I/II study using reduced doses of PTCY in transplant recipients from HLA-identical donors [32]. Following a 3 + 3 dose escalation design, they analyzed the results of PCTY 50 mg/kg/day on days + 3/+4, 50 mg/kg on day + 3 and 25 mg/kg on day + 4, or 25 mg/kg on days + 3/+4. Overall, none of the 29 patients enrolled in the study developed grade III-IV acute GVHD at 100 days. In patients who received PCTY at a dose of 25 mg/kg/day on days + 3/+4, the incidence of grade II-IV acute GVHD at day + 100 was 28.6%. Although this incidence was similar among the three groups of PCTY doses, it appears to be somewhat higher than that observed in our study, suggesting that the optimal dose of PCTY in combination with a single immunosuppressant (CsA or Tac) may be between 25 mg/kg/day and 40 mg/kg/day on days + 3/+4.
Overall, the results of all these studies, together with our findings, suggest that the intensity of immunosuppression could be reduced, both the dose of PCTY and the number of immunosuppressive drugs associated with it, when PBSC grafts from HLA-matched donors are infused for allo-HCT. Nevertheless, further studies are needed to determine PCTY appropriate dose and combination.
PTCY is associated with adverse effects including engraftment and immune reconstitution delays, increased risk of infection, and cardiac complications [10–18], suggesting the need for dose adjustment to reduce toxicity while maintaining efficacy in preventing GHVD. In a recent study, we showed that PTCY 50 mg/kg/day on days + 3/+4 was associated with delayed neutrophil and platelet engraftment compared to non-PTCY regimens (20 vs. 16 days and 19 vs. 12 days, respectively) [9]. In the present study, neutrophil and platelet engraftment occurred more rapidly (median time of 15 and 16 days, respectively) than that previously reported with PTCY 50 mg/kg/day [9]. The systematic administration of G-CSF may have contributed to the faster recovery of neutrophils, but it did not affect platelet recovery. In addition, we did not observe any primary graft failure. Similarly, Dulery et al. found that reducing the PTCY dose in the context of haploidentical transplantation resulted in faster hematopoietic engraftment [16].
PTCY has been identified as an independent risk factor for bacterial bloodstream infection during early post-transplantation follow-up [12]. In our previous study, it was found that PTCY 50 mg/kg/day was associated with a day + 30 incidence of bacterial bloodstream infection of 43.2% [9]. The present results indicate that using PTCY 40 mg/kg/day can lower the risk of bacterial bloodstream infection, with a cumulative incidence within the first 100 days of 13.6%. We also observed that PTCY 50 mg/kg/day significantly prolongs patient hospitalization (median of 37 days) [9]. Based on the results of this pilot study, it appears that PTCY 40 mg/kg/day together with the addition of G-CSF may decrease hospitalization time to a median of 32 days.
Early cardiotoxicity induced by PTCY is also a matter of concern. Between 7.4% and 19% of early cardiac events have been reported with the use of PTCY [15, 16, 34]. In our series, with 72.7% of patients previously exposed to anthracyclines, the incidence of early cardiac events was lower (4.5% at 2 years) than that reported by other authors [15, 16, 34].
Our study is limited by the small cohort size and relatively short follow-up. However, it is worth noting that unlike other studies that used reduced doses of PTCY in combination with two or three immunosuppressive drugs, our study only used Tac in combination with PTCY and achieved optimal prevention of acute GVHD. Further analysis with a larger patient sample size and longer follow-up will be performed in the ongoing study to confirm the reported observations.
In conclusion, this pilot study shows that PTCY 40 mg/kg/d on days + 3/+4 together with Tac appears to be an acceptable dose reduction in the setting of PBSC MRD and MUD alloHSCT. This strategy may reduce toxicity and improve hematopoietic and immune reconstitution while maintaining GVHD prevention.