ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THERAPY-RELATED MYELOID NEOPLASMS (t-MN) OF THE ADULT: MONOCENTRIC OBSERVATIONAL STUDY AND REVIEW OF THE LITERATURE.
Sica

Allogeneic Hematopoietic Stem Cell Transplantation In Therapy-Related Myeloid Neoplasms (t-MN) of the Adult: Monocentric Observational Study and Review of the Literature

Elisabetta Metafuni, Patrizia Chiusolo, Luca Laurenti, Federica Sorà, Sabrina Giammarco, Andrea Bacigalupo, Giuseppe Leone and Simona Sica.

Hematology Department, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy.

Corresponding author: Prof. Simona Sica. Hematology Department, Fondazione Policlinico Agostino Gemelli, Largo Agostino gemelli, 8 00168, Rome, Italy. Tel. 0039 0630155300/6016 Fax: 0039 063017319. E-mail: simona.sica@unicatt.it  

Published: January 1, 2018
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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This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: Therapy 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.
Methods: We describe a cohort of 30 patients, 18 females and 12 males, with median age of 52.5 years (range, 20 to 64), submitted to allogeneic stem cell transplantation (HSCT) in our department between September 1999 and March 2017. Patients had a history of solid tumour in 14 cases, haematological disease in 15 cases and both of them in one case. After a median of 36.5 months (range, 4 to 190) from first neoplasm, patients developed t-AML in 19 cases and t-MDS in 11 cases. Molecular abnormalities were detected in 5 patients, while karyotype aberrations were found in 17 patients. Patients received conventional chemotherapy in 14 cases, azacitidine in 10 cases and both of them in one case. Five patients were submitted to HSCT without previous treatment except for supportive therapy.
Results: Seventeen patients obtained sustained CR after SCT, while 8 patients showed resistant or relapsed disease. The remaining five patients died early after SCT. At follow up time (May 2017) 13 patients were alive with a median OS of 48 months (range 3-195), while 17 patients died after a median of 4 months (range 1-27) by relapse mortality in 6 cases and non-relapse mortality in the other 11 patients.
Conclusions: Global OS was 43%. After SCT, 72.2% of patients with t-MN maintained a sustained CR.

Introduction

Therapy-related myeloid neoplasms are recognized as a separate entity in the World Health Organization (WHO) classification of haematological diseases.[1] The incidence of therapy-related myeloid neoplasms (t-MN) continue to rise due to the relative prolongation of survival and cure related to chemo- and radio-therapy for primary malignancies, mostly breast cancer and lymphoproliferative diseases.[2-7]The peak occurrence time of therapy-related acute myeloid leukemia/myelodysplastic syndrome is 3 to 5 years after prior cytotoxic treatment, while the risk decreases markedly after the first decade.[8] At present, t-MN account for 10–20% of all malignant myeloid diseases.[9] Factors associated with an increased risk of t-MN include exposure to alkylating agents, topoisomerase II inhibitors, radiation therapy,[10-15] and older age at treatment, in addition to genetic susceptibility.[16-21] t-MN after anthracyclines and/or topoisomerase II inhibitors are associated with occurrence of MLL translocation at 11q23 or RUNX1/AML1 at 21q22 after a median latency of 1 to 3 years without a prodromal phase. t-MN after alkylating agents have a median latency of 4 to 10 years and are often preceded by myelodysplasia. It is associated with unbalanced chromosome 5 and 7 abnormalities, complex karyotypes, and/or TP53 mutations. After radiation treatment, the highest risk for t-MN occurrence is registered at 2 years and appears to normalize after 10 to 15 years.[22-24] Particularly, patients who received radiation to chest, pelvis and vertebrae for stomach, colorectal, liver, breast, endometrial, prostate, and kidney cancers seem to be at a significantly higher risk of developing t-MN.[24,25] More recently, it came to light the potential role of various germline genetic factors in an individual’s susceptibility to t-MN, particularly for those variants that alter drug metabolism such as gene NQ01, glutathione-S-transferase,[9,18,19,26] as well as those involved in DNA repair pathway such as BRCA, TP53 and MDM2.[20,21]
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

Allogeneic haematopoietic stem cell transplantation (HSCT) represents the only potentially curative strategy, but it is not feasible for all patients due to age, comorbidities in elderly patients, poor organ reserve and high non-relapse mortality (NRM).[4,45] The haematopoietic cell transplantation-specific comorbidity index (HCT-CI) was developed as a sensitive tool to measure the burden of comorbidities before HSCT and to predict both the risks of NRM and the probabilities of survival after HSCT.[46] As reported by ElSawy et al.[47] in the HCT-CI validation study, the three HCT-CI risk groups with score 0, 1–2, and ≥3 result in a NRM of 14%, 23%, and 39% with a survival of 74%, 61%, and 39%, respectively. Therefore, HSCT should be offer as a reliable option to fit patients with good performance status, intermediate and poor risk karyotype with suitable and available donor.[9,27,28,48-50] With particularly interest to t-MN, the Center of International Bone Marrow Transplantation Research (CIBMTR) and the European Group for Bone and Marrow Transplantation (EBMT) extrapolated pre-transplant factors predicting post-HSCT outcome in these patients from larges study cohorts. CIBMTR conducted a large study cohorts on t-MN and proposed a prediction model of survival after allogeneic HSCT using the following four risk factors: age older than 35 years, poor-risk cytogenetics, t-AML not in remission or advanced t-MDS, donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50%, 26%, 21%, 10%, and 4%, respectively.[27] Also the EBMT group[28] reported that disease stage at transplant different from complete remission, abnormal cytogenetics (excluding t(8;21), inv(16) and t(15;17)) and patients’ age >40 years are the most significant factors predicting survival, relapse rate, disease-free survival (DFS) and NRM dividing patients into three risk groups: low, intermediate and high. Overall survival for the above-mentioned groups was 62%, 33% and 24%, respectively; DFS was 58% (low), 32% (intermediate) and 20% (high); NRM was 22% (low), 37% (intermediate) and 38% (high); finally, relapse rate was 20% (low), 31% (intermediate) and 32% (high) respectively.
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 Table 1. Results of the review: outcomes of patients with therapy-related AML/MDS submitted to HSCT. 

Monocentric Observational Study

Patients and disease characteristics. We retrospectively analyzed patients submitted to HSCT in our department and identified 30 patients with a diagnosis of therapy-related myeloid neoplasm (t-MN) transplanted between September 1999 and March 2017. Patients were 18 females (60%) and 12 males (40%) with a median age of 52.5 years (range, 20 to 64). Secondary neoplasm was acute myeloid leukemia (t-AML) in 19 cases (63%) and myelodysplasia (t-MDS) in 11 cases (37%). Data were collected through retrospective chart review and after institutional review board approval. The median time occurred from primary disease to t-MN occurrence was of 36.5 months (range, 4 to 190). Primary disease was hematologic in 15 cases (50%): Hodgkin’s disease (n=2), non-Hodgkin’s lymphoma (n=9), acute lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=2) and acute myeloid leukemia (n=1). Fourteen patients (50%) had a previous diagnosis of solid tumor: medulloblastoma (n=1), breast (n=8), Ewing sarcoma (n=1), thyroid (n=1), bladder (n=2) and vagina/anus (n=1). One patient had a history of both haematological (non-Hodgkin's lymphoma) and solid tumor (breast). Twelve patients (40%) had been previously treated with chemotherapy, 8 patients (26.7%) with chemotherapy and autologous transplantation, 2 (6.7%) patients with radiotherapy, one patient (3.3%) with radioiodine therapy and 7 patients (23.3%) with a combination of chemo- and radiotherapy. At t-MN diagnosis all patients had received a median of 2 lines of therapy (range, 1 to 6) for their primary malignancy. All patients were free of their primary malignancies at the time of transplantation.
Revised International Prognostic Scoring System (IPSS-R)[63] was used to classify cytogenetics of t-MDS, while European Leukemia Net AML risk stratification by cytogenetics was used for AML.[64] 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 Table 2.  Detailed report of patients, primary and therapy-related disease and treatment.

Table 3 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.

Results

Engraftment and GvHD. White blood cells count of ≥1.0x109/L and stable platelets count ≥20.0x109/L were reached at median day +21 (range, 11 to 130) and median day +15 (range, 10 to 45), respectively. Three patients died early before achieving stable engraftment.
Acute GvHD (aGvHD)[65] 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)[66] 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.
Figure 1

Figure 1. Five-years outcomes of therapy-related AML/MDS after HSCT: 1A) Kaplan Meier for DFS; 1B) Kaplan Meier for OS; 1C) cumulative incidence of NRM; 1D) cumulative incidence of RRD; 1E) Kaplan Meier for OS according to cGvHD development; 1F) Kaplan Meier for OS according to relapse occurrence; 1G) cumulative incidence of NRM according to transplant conditioning regimen; 1H) cumulative incidence of RRD according to cGvHD development.

Discussion

In the last two decades, many authors published results concerning different cohorts of patients with therapy-related acute myeloid leukemia or myelodysplasia submitted to allogeneic stem cell transplantation. An high heterogeneity in the percentage of OS (22% to 66%), NRM (21% to 58%) and relapse rate (26% to 42%) come to light from these experience.[2,27,28,38,51-62] Each of these studies highlighted a different key point in this transplant setting, which might affect outcome after HSCT. The mainly predicting factor for OS resulted the karyotype and the recipient performance status at transplant.[38,54,56] Patients achieving a CR before transplantation showed better outcomes, whereas multiple therapy lines increase organ damage as well as the incidence of neutropenia, infection events and the immunosuppression of the patient increase TRM.[54,60,61] Patients at risk for treatment-related myeloid neoplasms should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia.[38,58,61] Considering the incremented risk of relapse according to blasts percentage, patients with secondary MDS should be direct to transplantation before the progression into AML, and if secondary AML occurs, they should be transplanted as soon as possible.[61] For patients who did not achieved a CR pre-transplant, rapid transplantation, also considering alternative donor, could offer a reasonable outcome, reducing the risk of deterioration of the patient’s performance status. OS after HSCT in patients aged 60 years or above was very poor.[50,51,67,68] Reduced intensity conditioning and conditioning with targeted busulphan dose[38,51,58] might reduce TRM, especially for those patients with a reduced organ reserve. As reported for patients with de novo MDS,[69] pre-transplant disease stage, cytogenetic risk group,[57,56] type of therapy given for the original disease, transplant conditioning regimen, and patient age[61] significantly affect relapse-free survival among patients with secondary MDS/t-AML.[38] Concerning to stem cell source, peripheral blood instead of bone marrow appeared to reduce NRM38 and relapse rate[38,57] and to improve OS.[38] On the other hand, controversial data were reported relative to donor source impact on OS.[2,27,38,53,70]
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.[71] 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.

Conclusions

The incidence of t-MN is increasing as more individuals survive treatment for a primary cancer diagnosis. At t-MN diagnosis,[72] physicians should evaluate molecular and cytogenetic risk of the disease, performance status, age and comorbidities of patients, and should start HLA-typing to timely detect a suitable donor. Older patients with poor performance status should be offered clinical trials or best supportive care. For fit patients, molecular and cytogenetics stratification is crucial. t-APL might benefit from standard first line protocols. Favorable karyotype t-MN should be treated with standard induction chemotherapy followed by high dose cytarabine consolidation course. Normal karyotype t-MN could receive standard induction chemotherapy followed by HSCT while poor molecular karyotype t-MN should be encouraged to participate in prospective clinical trials specifically designed and they should be considered early for allogeneic HCT.[51] Upfront HSCT could be offered to patients with low blast count and poor performance status.

Acknowledgements

This study was supported by Centro di Ricerca sulle Cellule Staminali Emopoietiche e le Terapie Cellulari, Università Cattolica del Sacro Cuore in Rome.

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