Allogeneic Hematopoietic Stem Cell Transplantation In Therapy-Related Myeloid Neoplasms (t-MN) of the Adult: Monocentric Observational Study and Review of the Literature
Received: October 10, 2017
Accepted: Dicember 1, 2017
Mediterr J Hematol Infect Dis 2018, 10(1): e2018005 DOI 10.4084/MJHID.2018.005
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related myeloid neoplasms (t-MN) occur due to direct mutational events
of chemotherapeutic agents and radiotherapy. Disease latency,
mutational events and prognosis vary with drugs categories.
Clonal cytogenetic abnormalities are found in 75–90% of t-MN, and 46-70% of them are adverse karyotype including complex karyotype, deletion or loss of chromosome 5 and/or 7.[3,4] Cytogenetics assessment is the principal prognostic factor for relapse rate and overall survival (OS).[27-29] The heterogeneous treatments of therapy-related myeloid neoplasms, ranging from best supportive care to intensive chemotherapy, hypomethylating agents, and allogeneic stem cell transplantation, do not allow definite conclusions on the best treatment choice, particularly for elderly patients.[30,31] Treatment of t-MN with conventional therapy is associated with a poor outcome in terms of survival (6 months),[8,32] remission rate (28% to 50%) and duration of the remission.[33-35] On the other hand, conventional chemotherapy might be a reasonable option for t-MN with favourable karyotype such as inv(16), t(16;16), t(15;17) or t(8;21), since the reported remission rate and the disease free survival are similar to those seen for the de novo counterpart.[35,36] The introduction of new drugs such as azacitidine and decitabine has shown promising results in the management of t-MN with an acceptable toxicity profile also for frail patients, and with an overall response rate of approximately 40%.[4,30,31,37-44]
Allogeneic Stem Cell Transplantation for t-MN
We performed a review of the literature on therapy-related AML/MDS submitted to allogeneic stem cell transplantation excluding AML secondary to MDS progression. Detailed results concerning cohort size, median follow up, overall survival, NRM incidence, and relapse rate are depicted in Table 1. The reported outcomes for patients submitted to HSCT for therapy-related AML/MDS are very heterogeneous. Median OS ranges from 22% to 66%, with a NRM of 21 to 58% and a relapse rate of 26% to 42%.[2,27,28,38,51-62]
|Table 1. Results of the review: outcomes of patients with therapy-related AML/MDS submitted to HSCT.|
Monocentric Observational Study
Revised International Prognostic Scoring System (IPSS-R) was used to classify cytogenetics of t-MDS, while European Leukemia Net AML risk stratification by cytogenetics was used for AML. Karyotype was available for 28 out of 30 patients. Eleven patients (36.7%) had normal karyotype, three patients (10%) had a favourable karyotype, 5 patients (16.7%) had an intermediate-risk karyotype and 9 patients (30%) had an adverse-risk karyotype. Molecular cytogenetics analyses were available for 14 out of 30 patients: FLT3/ITD+ (n=2), CBFB/MYH11 (n=1), NPM1+ (n=1), NPM1 and FLT3/ITD double positivity (n=1), no abnormalities (n=9). A detailed description of primary neoplasms, treatment for primary neoplasm and t-HN is reported in Table 2. Transplant features and outcomes are depicted in Table 3.
|Table 2. Detailed report of patients, primary and therapy-related disease and treatment.|
|Table 3. Transplant for t-MN: features and outcomes.|
Statistical analysis. Overall survival and disease-free survival (DFS) were estimated using Kaplan-Meier product method, while for curves comparison log-rank test was applied. χ2 test and Fisher’s exact test were used to assess associations between categorical variables and OS, NRM, RRD, DFS. A competing risk analysis was performed to calculate the cumulative incidence of relapse-related death (RRD) and non-relapse mortality (NRM). For NRM, relapse was the competing event, and for relapse, NRM was the competing event. Fine and Gray’s method for cumulative incidence of RRD and NRM were used to compare different groups. Statistical analysis was realized using NCSS 10. A p-value ≤ 0.05 was considered statistically significant.
Acute GvHD (aGvHD) occurred in 15 patients (50%) and global grading was as follows: grade I (n=3), grade II (n=5), grade III (n=6), and grade IV (n=1). Among them, three patients died because of aGvHD. Chronic GvHD (cGvHD) was diagnosed in 14 out of 23 patients surviving after day +100 (65%) and global scoring was as follows: mild (n=3), moderate (n=7) and severe (n=4). One of them died for cGvHD-related complications.
Response. Morphological bone marrow cytology was performed on day +30 after HSCT only in 25 patients because of early death in the others five. Three patients (12%) had a persistence of the underlying disease, whereas twenty-two patients achieved a CR (88%) on day +30. Among them, 5 patients (22.7%) experienced a relapse after a median time of 6 months (range, 3 to 15), while 17 patients (77.3%) maintained a CR after a median time of 27 months (range, 3 to 195). Median 2-ys DFS after HSCT was of 72.2% (95% CI 51.1 to 93.3) (Figure 1A).
Overall survival, NRM and RRD. At the follow up data fixed on May 2017, 13 patients were alive after a median time of 48 months (range, 3 to 195), while 17 patients died after a median time of 4 months (range, 1 to 27). The causes of death were as follows: underlying disease (n=6), GvHD (n=3), EBV-related post-transplant lymphoproliferative disease (PTLD) (n=1) and infectious complications (n=7). The overall survival at 2 years after HSCT was of 40.5% (95% CI 22.1 to 58.9), whereas the cumulative incidence of NRM and RRD at 2 years was of 44.4% (95% CI 27.6 to 71.2) and 29.6% (95% CI 15 to 58.6), respectively (Figures 1B, 1C and 1D). No differences in terms of OS, NRM, RRD and DFS were seen stratifying patients according to underlying disease, disease status at transplant, previous treatment received, karyotype risk, patients and donor characteristics, stem cell source. An association was identified between OS and cGvHD development after HSCT, as well as between OS and relapse occurrence. Overall survival was higher in the group with cGvHD than those detected in the group without this complication (68% vs. 22%, p=0.018). Median OS was of 6 months (range, 4.6 to 7.4) in the group without cGvHD, while it was not reached in the group with cGvHD (p=0.0002, Figure 1E). An higher mortality was recorded in the group of patients who experienced a relapse of the underlying disease as compared with patients who did not relapsed after HSCT (67% vs. 13%, p=0.011). Median OS in the group relapsed after HSCT was of 5 months (range, 2.2 to 7.8) as compared to patients without relapse, for whom a median OS was not reached (p=0.004, Figure 1F). Relatively to NRM, an association was identified with the conditioning regimen: surprisingly, NRM was higher for patients who had received a reduced intensity conditioning as compared to those who had received a myeloablative one (p=0.046). Two-years cumulative incidence of NRM was of 74% (95% CI 49 to 100) after RIC transplant and 24% (95% CI 10 to 58) after ABL transplant (p=0.022, Figure 1G). Finally, also for RRD an association was found with cGvHD development after HSCT: among patients with cGvHD, a minor number of RRD was recorded as compared to patients who had not developed this complication (p=0.018). The cumulative incidence of RRD at 2 years after HSCT was of 9% (95% CI 1 to 59) for patients with cGvHD and 65% (95% CI 38 to 100) for patients without cGvHD (p=0.004, Figure 1H).
Two patients (6.7%) experienced a third tumor, in particular a breast cancer occurred thirteen years after HSCT and an EBV-related PTLD of the brain occurred eight months after HSCT.
In our cohort, global OS appeared to fit with those reported from several authors (40.5% vs 22-66%), whereas NRM appeared the major cause of death, even if the NRM rate was comparable to others data (44% vs 21-58%).[2,27,28,38,51-62] Surprisingly, we observed an high DFS (72.2%) perhaps attributable to high cGvHD rate after HSCT, corresponding to an enhanced GvL effect. In fact, among patients with cGvHD a reduced RRD and an increased OS were registered. Graft-versus leukemia (GvL) effect, especially associated with chronic GvHD, improved DFS and OS also in adverse karyotype t-MN submitted to HSCT. Probably due to the small size of our study group, no differences in terms of post-transplant outcomes emerged dividing patients according to recipient age, previous treatment, disease status at transplant, karyotype, donor or stem cell source. Unexpectedly, we found a higher NRM among patients who had received a RIC transplant as compared to ABL, but no differences in performance status, pre-transplant risk score or disease status existed between the two groups.
An interesting feature revealed by our curves was that DFS reached a plateau approximately after the first year post HSCT, while OS reached its prolonged plateau after the second one. In fact, no relapse was ascertained after the first year post-HSCT, so that eighteen patients (56.7%) obtained and maintained a complete remission after HSCT. On the other hand, no deaths were recorded after the second year post-HSCT, with an OS of 40.5% at the follow up time.
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