For patients with acute leukemia who relapse after the first allogeneic transplantation (hematopoietic stem cell transplantation 1 (HSCT1)), the choice of curative treatments is limited, and includes mainly DLI and a second allogeneic transplantation (HSCT2). If the patient fails salvage treatment and the BM blast count remains high, long-term disease-free survival is highly unlikely to be achieved using DLI1 and a second allogeneic transplant is probably the only curative treatment for the very high-risk patient. For the second allogeneic transplantation, the donor can be the same as for the HSCT1, a HLA-matched sibling (MSD) or unrelated donor (MUD), or even HLA-mismatched alternative donors. Of these, the use of a HLA-haploidentical donor would be of particular advantage for the high-risk patient, in that it is easier and rapidly available and would have a potentially stronger GVL effect compared with other donors;2, 3 however, the risk of graft failure and GVHD remains a great concern. Tischer et al.4 recently published an elegant study on using haploidentical HSCT2 for the treatment of 20 patients with relapsed acute leukemia after allogeneic HSCT1. Here, we report our experience using haploidentical transplantation for the treatment of five consecutive patients with acute leukemia who relapsed after the first allogeneic transplant. The differences in the procedure and outcome between our study and the study by Tischer et al.4and the potential clinical implication are discussed.
For HSCT1, all the patients received myeloablative conditioning except case no. 5, a patient who received reduced-intensity conditioning (RIC) because of old age. The stem cell sources were PBSCs from a MSD in case no. 2 and a MUD or mismatched MUD for the other four patients. According to the regulations of Buddhist Tzu Chi Stem Cells Center, the only marrow donor registry in Taiwan, donors of PBSCs can donate only once in their lifetime. Also, the original sibling donor in case no. 2 refused to donate SCs again. As no other HLA-matched donor was available, a haploidentical donor was the only choice for these patients (Table 1).
For HSCT2, the five patients received RIC regimens, considering the fact that they were all heavily pretreated. Cases no. 2, 3 and 4 had >50% blasts in the BM before the second transplant. They underwent a sequential strategy consisting of short-course cytoreductive chemotherapy aimed at reducing the leukemic burden (clofarabine and CY in cases no. 2 and 4; mitoxantrone, etoposide and Ara-C in case no. 3), immediately followed by conditioning chemotherapy or chemoradiotherapy for HSCT2. Bone marrow aspiration after cytoreductive chemotherapy showed marked hypocellularity with no excess of blasts in these 3 patients. All 5 patients received standard antibiotic (ciprofloxacin) and anti-fungal (micafungin) prophylaxis. Case no. 4 developed aspergillus pneumonia before transplantation and was given voriconazole during the whole HSCT2 course. GVHD prophylaxis consisted of post-transplant high-dose CY (PTCy; 50 mg/kg i.v.) on Days +3 and +4, a strategy introduced by the Baltimore group,5 followed by CYS and mycophenolate sodium started on Day +5. Low-dose antithymocyte globulin (rabbit ATG, thymoglobulin 3.5–4.5 mg/kg) from Days −4 to −2 was added additionally to prevent GVHD, because the use of G-CSF mobilized PBSCs in this study, rather than the BM used as a stem cell source in most haploidentical HSCTs using a PTCy strategy. Cases no. 2 and 4 had a very high blast counts in BM before HSCT2, so ATG and CYS were replaced by short-course sirolimus to enhance the anti-leukemic and possibly GVL effect.6 The EBV and CMV viral load (or CMV pp65 antigenemia) were tested weekly after HSCT2. Ganciclovir was given as a pre-emptive treatment for patients with CMV reactivation.
All patients achieved complete donor chimerism and had successful neutrophil and platelet engraftment after haploidentical HSCT2. There was no grade 3/4 acute GVHD and only one patient had extensive chronic GVHD, which is now under control with low-dose steroid. Case no. 1 had relapse of leukemia 6 months after HSCT2; the patient received a third HSCT from the same haploidentical donor (NIMA-mismatched sister) and achieved a third remission. Ten months after HSCT3, the leukemia relapsed again and she received a fourth HSCT from her mother and had a fourth CR with full donor chimerism. She is now under monthly azacitidine treatment to prevent further relapse of leukemia. Two patients (cases no. 1 and 2) had documented bacterial infection (Clostridium difficile colitis and Escherichia coli bacteremia, respectively). Two patients (cases no. 3 and 5) had CMV reactivation and were successfully treated with pre-emptive ganciclovir. Three ATG-treated patients (cases no. 1, 3 and 5) had EBV reactivation, but only one patient (case no. 3) needed pre-emptive rituximab treatment. There was no documented invasive fungal infection during HSCT2 based on EORTC/MSG criteria.7 All the patients were alive and disease-free at the last follow-up.
In the study by Tischer et al.,4 20 consecutive patients with relapsed acute leukemia after allogeneic HSCT1 were treated with a second haploidentical HSCT using a PTCy strategy. The researchers concluded that haploidentical HSCT2 is feasible, with acceptable rates of toxicity and non-relapse mortality. Our results are consistent with the study by Tischer et al.4 Compared with the median 29 days for neutrophil engraftment in the study by Tischer et al.,4 our time to neutrophil engraftment was faster, with a median of 15 days (range 11–15) in the seven haploidentical PBSCT (including the third and fourth transplants for case no. 1) of our five patients. This data is exactly the same as that of another 15 patients receiving haploidentical HSCT1 using the same protocol consisting of a RIC regimen, PTCy strategy and PBSC as a stem cell source (median 15 days, range 11–19). Furthermore, thanks to the rapid neutrophil engraftment, no new or lethal fungal infection was noted during HSCT2 in our patients, compared with the 60% fungal infection rate and 20% death rate due to fungal infection by Day 100 in the study by Tischer et al.4 The earlier neutrophil engraftment and absence of fungal infection in our study are likely due to the use of PBSC as a stem cell source, while 70% of the patients in the study by Tischer et al.4 received BM. The incidence and severity of GVHD in our patients were actually lower than expected, despite the use of PBSC as a stem cell source, as there was no grade 3/4 acute GVHD and only one extensive chronic GVHD. A similar result was reported in the study by Solomon et al.,8 showing that the incidence of acute and chronic GVHD in haploidentical PBSCT using a PTCy strategy was comparable, if not slightly less than expected with allogeneic PBSCT from HLA-matched donors.
In conclusion, a second haploidentical HSCT using a RIC regimen and PBSC as a stem cell source is safe and feasible for patients with acute leukemia who relapse after allogeneic HSCT1. Although the patient number is too small to draw a definite conclusion, our data suggest that neutrophil engraftment is fast, and GVHD and infectious complications are not severe with this approach. Frequent EBV and CMV reactivation is anticipated and is easily managed if the patient is regularly monitored. Of course, more patients and longer follow-up are needed to verify the efficacy and long-term toxicity. In addition, more studies are needed to optimize the conditioning regimen, as well as the dose of ATG, to further improve the outcome of haploidentical HSCT2.
Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007; 25: 4938–4945.
Dong L, Gao ZY, Yu XJ, Tan XY, Lui JH, Lu F et al. HLA disparity is associated with improved outcomes in hematological malignancies after family HLA-mismatched / haploidentical HCT but not URD. ASH Annu Meet Abstr 2012; 120: 2014.
Kanda Y, Chiba S, Hirai H, Sakamaki H, Iseki T, Kodera Y et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991–2000). Blood 2003; 102: 1541–1547.
Tischer J, Engel N, Fritsch S, Prevalsek D, Hubmann M, Schulz C et al. Second haematopoietic SCT using HLA-haploidentical donors in patients with relapse of acute leukaemia after a first allogeneic transplantation. Bone Marrow Transplant 2014; 49: 895–901.
Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650.
Cieri N, Greco R, Morelli M, Giglio F, Assanelli A, Forcina A et al. Post-transplant cyclophosphamide haplo-HSCT revised: peripheral blood stem cell graft and sirolimus to enhance immune reconstitution and graft versus leukemia effect in patients with active leukemia. ASH Annu Meet Abstr 2013; 122: 2118.
De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–1821.
Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK et al. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who Lack conventional donors is well tolerated and produces excellent relapse-free Survival: results of a prospective phase II trial. Biol Blood Marrow Transplant 2012; 18: 1859–1866.
We are grateful to all of the nursing staff at the 5H BMT unit of CMUH for their excellent care of our transplant patients.
This work was supported in part by research grants from the Taiwan National Science Council (NSC-101-2321-B-039-005 to S-PY) and the China Medical University Hospital (DMR-99-010 to S-PY). The remaining authors declare no conflict of interest.
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Outcome and prognostic factors among patients who underwent a second transplantation for disease relapse post the first allogeneic cell transplantation
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