Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

Number: 0836

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for myelodysplastic syndrome.

1. Medical Necessity

   1. Aetna considers allogeneic (ablative and non-myeloablative) hematopoietic cell transplantation medically necessary for individuals with intermediate-risk or high-risk myelodysplastic syndrome (MDS), and who have not responded to prior therapy and have an available human leukocyte antigen (HLA)-compatable donor.
   2. Aetna considers a repeat allogeneic (ablative or non-myeloablative) hematopoietic cell transplantation medically necessary for individuals with intermediate-risk or high-risk MDS due to primary graft failure, failure to engraft, or late relapse (greater than 18 months after HCT) (salvage therapy).

2. Experimental and Investigational

   1. Aetna considers a repeat allogeneic (ablative or non-myeloablative) hematopoietic cell transplantation experimental and investigational for individuals with MDS who early relapse.
   2. Aetna considers autologous hematopoietic cell transplantation experimental and investigational for individuals with MDS because the effectiveness of this approach for this indication has not been established.

3. Related Policies

   • CPB 0634 - Non-myeloablative Hematopoietic Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met :
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic
38230	Bone marrow harvesting for transplantation; allogeneic
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38242	Allogeneic lymphocyte infusions
CPT codes not covered for indications listed in the CPB:
38206	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous
38232	Bone marrow harvesting for transplantation; autologous
38241	Hematopoietic progenitor cell (HPC); autologous transplantation
Other CPT codes related to the CPB:
38204, 38207 - 38220	Bone marrow or stem cell services/procedures
86813	HLA typing; A, B or C multiple antigens
86817	DR/DQ, multiple antigens
86821	lymphocyte culture, mixed (MCL)
Modifier 4A - 4Z	Histocompatibility/blood typing/identity/microsatellite
HCPCS codes covered if selection criteria are met:
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
ICD-10 codes covered if selection criteria are met:
D46.0 - D46.9	Myelodysplastic syndromes (MDS)

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Background

Laport et al (2008) stated that allogeneic stem cell transplantation (ASCT) is the only curative strategy for patients with MDS and myelo-proliferative disorders (MPD).  These researchers reported the results of 148 patients (median age of 59 years old) with de novo MDS (n = 40), AML after antecedent MDS/MPD (n = 49), treatment-related MDS (t-MDS) (n = 25), MPD (n = 27), and chronic myelo-monocytic leukemia (CMML) (n = 7) who underwent ASCT using a conditioning regimen of low-dose total body irradiation (TBI) alone (200 cGy) on day 0 (n = 5) or with the addition of fludarabine 30 mg/m(2)/day on days -4 to -2 (n = 143).  Post-grafting immunosuppression consisted of cyclosporine and mycophenolate mofetil.  A total of 75 patients (51 %) received an allograft from a matched-related donor (MRD), and 73 patients (49 %) were recipients of unrelated donor (URD) grafts.  There was no significant difference in the incidence of acute (grade II to IV) and chronic graft-versus-host disease (aGVHD, cGVHD) between the recipients of related and unrelated donor grafts.  By day +28, 75 % of patients demonstrated mixed T cell chimerism.  Graft rejection was seen in 15 % of patients.  With a median follow-up of 47 (range of 6 to 89) months, the 3-year relapse-free survival (RFS) and OS were both 27 % for all patients, with a relapse incidence of 41 %.  The 3-year RFS for the patients with de novo MDS, AML after antecedent MDS/MPD, t-MDS, MPD, and CMML were 22 %, 20 %, 29 %, 37 %, and 43 %, respectively, and the 3-year OS was 20 %, 23 %, 27 %, 43 %, and 43 %, respectively.  The 3-year non-relapse mortality (NRM) was 32 %.  Factors associated with a lower risk of relapse were the development of extensive cGVHD and having a low-risk or intermediate-1 risk IPSS for the de novo MDS patients.  Non-myeloablative HSCT confers remissions in patients who otherwise were not eligible for conventional HSCT, but for whom relapse is the leading cause of treatment failure.

Kindwall-Keller and Isola (2009) noted that HSCT is the only curative therapy for MDS; and numerous myeloablative (MA), non-myeloablative (NMA) SCT and reduced intensity conditioning (RIC) transplant studies have included MDS patients.  A total of 24 MA HSCT studies published from 2000 and 2008 reported OS and disease-free survival (DFS) ranging from 25 % and 16 % at 2 years to 52 % and 50 % at 4 years.  In these publications, the incidence of grades II to IV aGVHD was 18 % to 100 %, cGVHD 13 % to 88 %, relapse risk 24 % at 1 year to 54.5 % at 4 years and treatment-related mortality (TRM) 19 % at day 100 to 61 % at 5 years.  From 2003 to 2008, 30 publications combining RIC and NMA HSCT reported OS and DFS from 22 % and 20 % at 2 years to 79 % and 79 % at 4 years.  Incidence of grades II to IV aGVHD ranged from 9 % to 63 %, cGVHD 18 % to 80 %, relapse risk 6 % to 61 % and TRM 0 % at day 100 to 34 % at 5 years.  Although no ideal transplant conditioning has emerged, many of the MA and RIC studies used busulfan-based regimens and used a recipient age cut-off of 50 to 55 years for MA HSCT.  Similarly, there is no agreement on the use of induction or hypo-methylating therapy before HSCT, but azacitidine and decitabine are gaining increasing attention as a bridge to HSCT.  Until recently, the IPSS dictated the use and timing of HSCT.  The World Health Organization (WHO) classification and WHO Prognostic Scoring System (WPSS) may be better suited in predicting the outcomes and should probably be incorporated in transplant algorithms.  Most published MDS transplant series combine MRD and matched unrelated donors (MUD).  Umbilical cord blood (UCB) grafts will likely broaden the population of MDS patients eligible for allografting, but outcome data for MDS are scant.  At this time, it is reasonable to consider the availability of an MRD or MUD as separate from an UCB graft in the decision of transplantation for MDS.  The development of RIC, improvements in supportive therapy and alternative donor selection will provide better OS for MDS patients undergoing transplantation.  Simultaneously, better understanding and medical therapy of MDS are leading re-examination of patient selection and the timing of HSCT.

De Witte et al (2010) noted that ASCT is usually considered the only curative therapeutic option for patients with advanced or transformed MDS in CR, but post-remission chemotherapy and autologous SCT are potential alternatives, especially in patients over 45 years old.  These researchers evaluated, after intensive anti-leukemic RIC, the impact of the availability of a human leukocyte antigen (HLA)-identical sibling donor on an intention-to-treat basis.  Additionally, all patients without a sibling donor in CR after the first consolidation course were randomized to either autologous peripheral blood SCT or a second consolidation course consisting of high-dose cytarabine.  The 4-year survival of the 341 evaluable patients was 28 %.  After achieving CR, the 4-year survival rates of patients under 55 years old with or without a donor were 54 % and 41 %, respectively, with an adjusted hazard ratio (HR) of 0.81 (95 % CI: 0.49 to 1.35) for survival and of 0.67 (95 % CI: 0.42 to 1.06) for DFS.  In patients with intermediate-risk/high-risk cytogenetic abnormalities, the HR in multi-variate analysis was 0.58 (99 % CI: 0.22 to 1.50) (p = 0.14) for survival and 0.46 (99 % CI: 0.22 to 1.50) for DFS (p = 0.03).  In contrast, in patients with low-risk cytogenetic characteristics the HR for survival was 1.17 (99 % CI: 0.40 to 3.42) and that for DFS was 1.02 (99 % CI: 0.40 to 2.56).  The 4-year survival of the 65 patients randomized to autologous peripheral blood SCT or a second consolidation course of high-dose cytarabine was 37 % and 27 %, respectively.  The HR in multi-variate analysis was 1.22 (95 % CI: 0.65 to 2.27) for survival and 1.02 (95 % CI: 0.56 to 1.85) for DFS.  The authors concluded that patients with a donor and candidates for ASCT in first CR may have a better DFS than those without a donor in case of MDS with intermediate-risk/high-risk cytogenetics.  They stated that autologous peripheral blood SCT does not provide longer survival than intensive chemotherapy.

The American Society for Blood and Marrow Transplantation’s clinical guideline on "The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes" (2009) stated that based on data and expert opinion, a HLA-matched allogeneic donor (sibling, other family member, unrelated individual, or cord blood) SCT is recommended if an appropriate donor is available.  If an allogeneic donor is not available, and CR is achieved with induction therapy, then an autologous SCT can be considered in the context of a clinical trial.

The National Cancer Institute’s guideline on "Myelodysplastic Syndrome Treatment" (2011) stated that "Allogeneic bone marrow transplantation (BMT) for young patients with MDS offers the potential for long-term DFS.  In two large studies, 45 % to 60 % of patients with de novo MDS were projected to be long-term disease-free survivors.  Outcome tends to be better in younger patients with fewer bone marrow blasts, but long-term benefit has been noted in all FAB classification types, and in patients with marrow fibrosis, a variety of karyotypic findings, and different preparative regimens.  A retrospective review of outcomes of allogeneic BMT according to pre-transplant IPSS score showed that the IPSS score predicted relapse rate and DFS.  The 5-year DFS rates were 60 % for the low-risk and intermediate-1 risk group, 36 % for the intermediate-2 risk group, and 28 % for the high-risk group.  A review of 118 young MDS patients (median age of 24, age range of 0.3 to 53 years) who received allogeneic BMT from matched unrelated donors reported an actuarial survival of 28 % at 2 years.  Transplant-related mortality was influenced by the age of the patient (18 years or younger, 40 %; age of 18 to 35 years, 61 %; 35 years or older, 81 %).  Relapse rate was influenced by FAB classification.  This study included patients who received transplants as early as 1986, which may have influenced the patient survival data.  Outcomes may not be as good for patients with treatment-related MDS (5-year DFS of 8 % to 30 %) …. Allogeneic stem cell transplantation with non-myeloablative conditioning is under clinical evaluation for treatment of MDS.  A retrospective analysis of 836 allogeneic transplants for MDS using HLA-matched sibling donors was performed and included 215 patients who received non-myeloablative conditioning regimens.  The 3-year probabilities of progression-free survival and overall survival were similar in both groups (39 % after myeloablative conditioning versus 33 % in reduced intensity conditioning and 45 % versus 41 %, respectively; these differences were not significant).  Relapses were more common in the reduced intensity group, but non-relapse mortality was decreased".

Deeg and Bartenstein (2012) noted that ASCT offers potentially curative therapy for patients with MDS.  However, as the majority of patients with MDS are in their 70s or 80s, only few of these patients were transplanted following high-dose conditioning regimens.  The development of RIC has allowed ASCT to be used in older patients and those with clinically relevant co-morbid conditions.  Dependent upon disease status and the type of clonal chromosomal abnormalities present at the time of ASCT, 25 % to 75 % of patients will be cured of their disease and attain long-term survival.  Furthermore, recent results with HLA-matched unrelated donors are comparable to those with HLA genotypically identical siblings.

Luger et al (2012) stated that although RIC and NMA-conditioning regimens have been used for over a decade, their relative effectiveness versus MA approaches to ASCT in patients with AML and MDS is unknown.  These investigators compared disease status, donor, graft, and recipient characteristics with outcomes of 3,731 MA with 1,448 RIC/NMA procedures performed at 217 centers between 1997 and 2004.  The 5-year uni-variate probabilities and multi-variate relative risk outcomes of relapse, TRM, DFS and OS were reported.  Adjusted OS at 5 years was 34 %, 33 % and 26 % for MA, RIC and NMA transplants, respectively.  Non-myeloablative conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens.  Late TRM negates early decreases in toxicity with RIC and NMA regimens.  The authors concluded that these findings suggested that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft versus leukemia in these diseases.

An UpToDate review on "Hematopoietic cell transplantation in myelodysplastic syndromes" (Negrin, 2012) states that "a subset of patients with MDS can be cured following allogeneic hematopoietic cell transplantation (allo-HCT). Allo-HCT may be considered for patients with MDS less than 60 years of age with an HLA-matched sibling donor or a well matched unrelated donor.  The decision to pursue this aggressive form of therapy depends upon a number of criteria including the original or revised International Prognostic Scoring System MDS risk category, risk of disease progression, risk of infection, overall health of the patient, and the willingness of the patient to take on the risks associated with allo-HCT …. Non-myeloablative allogeneic HCT appears promising for patients with MDS who are not candidates for myeloablative allo-HCT.  Early results are encouraging in terms of reduced treatment-related mortality, although significant problems remain (e.g., increased relapse risk)".

The National Comprehensive Cancer Network’s clinical practice guideline on "Myelodysplastic Syndromes" (NCCN, version 2.2013) stated that "allogeneic HSCT from an HLA-matched sibling donor is a preferred approach for treating a selected group of patients with MDS, particularly those with high-risk disease.  Matched non-myeloablative transplant regimens and matched unrelated donor stem-cell transplants are becoming options at some centers to treat these patients.  In certain investigative settings, autologous bone marrow or peripheral blood stem cell transplantation is being considered.  Whether transplants should be performed before or after patients achieve remission following induction chemotherapy has not been established.  Comparative clinical trials are needed to determine these points". 

In a review on "Current therapy of myelodysplastic syndromes", Zeidan and, Linhares (2013) noted that the approval of azacitidine, decitabine, and lenalidomide in the last decade was a major breakthrough.  Nonetheless, the responses to these agents are limited and most patients progress within 2 years.  Allogeneic stem cell transplantation remains the only potentially curative therapy, but it is associated with significant toxicity and limited efficacy.

Saber et al (2013) stated that allo-HCT from HLA- MRD and MUD produces similar survival for patients with AML.  Whether these results can be extended to patients with MDS is unknown.  These investigators performed analysis of post-HCT outcomes for MDS.  Outcomes of 701 adult MDS patients who underwent HCT between 2002 and 2006 were analyzed (MRD [n = 176], 8 of 8 HLA-A, -B, -C, -DRB1 allele matched MUD [n = 413], 7 of 8 MUD [n = 112]).  Median age was 53 years (range of 22 to 78 years).  In multi-variate analyses, MRD HCT recipients had similar DFS and survival rates compared with 8 of 8 MUD HCT recipients (relative risk [RR] 1.13 [95 % CI: 0.91 to 1.42] and 1.24 [95 % CI: 0.98 to 1.56], respectively), and both MRD and 8 of 8 MUD had superior DFS (RR 1.47 [95 % CI: 1.10 to 1.96] and 1.29 [95 % CI: 1.00 to 1.66], respectively) and survival (RR 1.62 [95 % CI: 1.21 to 2.17] and 1.30 [95 % CI: 1.01 to 1.68], respectively) compared with 7 of 8 MUD HCT recipients.  The authors concluded that in patients with MDS, MRD remains the best stem cell source followed by 8 of 8 MUD; transplantation from 7 of 8 MUD is associated with significantly poorer outcomes.

An UpToDate review on "Hematopoietic cell transplantation in myelodysplastic syndromes" (Negrin, 2014) states that "Patients with MDS are at high risk for relapse (as much as 40 percent at five years) following allo-HCT.  Small numbers of patients who have relapsed have undergone donor leukocyte infusions in an attempt to utilize the graft-versus-disease effect.  Durable responses are not attained in most patients with MDS, and grade II to IV GVHD is common.  Alternative approaches are clearly needed".  The review does not mention repeat/second allo-HCT for patients who have relapsed.

The British Committee for Standards in Haematology’s guidelines for "The diagnosis and management of adult myelodysplastic syndromes" (Killick et al, 2014) states the following:

• Early allogeneic stem cell transplantation with or without prior AML-type induction chemotherapy should be considered for eligible patients with high-risk MDS.
• Patients who fail to respond to pre-transplant induction therapy should not undergo allogeneic stem cell transplantation and should be considered for experimental therapy or supportive care alone.
• Autologous stem cell transplantation for MDS is not recommended outside of clinical trials.

Moreover, the guidelines do not mention repeat/second allogeneic hematopoietic stem-cell transplantation (allo-HSCT).

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on "Myelodysplastic syndromes" (Version 1.2015) indicates that for MDS patients who relapse after allo-HSCT, azacitidine/decitabine or "clinical trial" is the next step.

A review of transplants for myelodysplastic syndromes (Wetzko and Platzbecker, 2014) explained: "Whether patients with advanced MDS actually benefit from an allogeneic SCT has only been studied in retrospective analyses with varying results. Prospective studies are lacking so far, but several studies have been initiated to compare allogeneic SCT and nontransplant among older patients with MDS. So far, an early allogeneic SCT is recommended for fit patients, with an available, compatible donor, up to 65 to 70 years of age at intermediate-2 and high-risk MDS according to IPSS, respectively, with very high, high, or intermediate risk referred to IPSS-R." Regarding the timing of transplant, the review stated that "[p]erforming allogeneic SCT immediately after diagnosis was shown to be superior in patients with higher-risk MDS, whereas younger patients with lower-risk MDS may benefit from delaying allogeneic SCT until progression of the disease. For patients with less advanced disease, however, an early transplant seems to be an overtreatment and exposes patients to a high risk of TRM."

Komrokji and colleagues (2016) stated that the higher risk MDS patients, defined by the IPSS as intermediate-2 or high-risk groups, compromise 1/3 of MDS patients who have an expected survival of less than 1.5 years. The ability to better define higher risk MDS improved with the proposal of new clinical risk models such as the revised IPSS and by integration of molecular data, including somatic gene mutations; AHSCT remains the only curative option.  In higher risk MDS patients, proceeding early with AHSCT is associated with maximum survival gain.  The decision to pursue AHSCT is individualized according to disease risk, co-morbidities, and functional status.  The role of therapy before AHSCT remains controversial, and the role of post-AHSCT maintenance is evolving.  Hypomethylating agents are the only medications that change the natural history of the disease.  Azacitidine is the only drug reported to improve OS in higher risk MDS patients.  Appropriate use and assessment of response is key for assuring patients benefit of such limited options.  Treatment after failure of hypomethylating agents is an unmet need.  The role of detectable somatic gene mutations in prognosis and tailoring therapy continue to emerge.

Relapse continues to be the major cause of failure after allogeneic HCT for MDS. Most patients who experience relapse do so within a short interval after HCT. However, late relapses occur and patients who relapse late may do so as a result of different pathogenic mechanisms. A study from Gerds, et al. (2012) suggest that in select patients with late relapse, a second transplant may provide a survival benefit. From 1984 to 2007, 961 patients underwent a first HCT for MDS (including RAEB-T and CMML) at a single institution, of whom 215 relapsed after HCT. The investigators analyzed results in the 44 patients whose relapse was diagnosed more than 1.5 years after HCT (median 2.62, range 1.83–20.53 years). Patients were 12–71 (median 45) years old and had been conditioned with either high- (91%) or reduced-intensity (9%) conditioning regimens. Donors were related (64%) or unrelated (36%); the graft source was marrow (55%), peripheral blood (43%), or cord blood (2%). The association of the patient, disease, and transplant parameters with time to relapse and survival after relapse was examined in univariate and multivariate analyses. The investigators reported that 5 patients relapsed with extramedullary disease, 4 without evidence of bone marrow involvement. The presence of chronic graft-versus-host-disease (cGVHD; HR = 0.48 [0.27–0.94, p = 0.04]) was associated with a longer delay of relapse. Both the presence of cGVHD (HR = 0.34 [0.14–0.83, p = 0.18]) and bone marrow as a source of stem cells (HR = 0.36 [0.17–0.74, p = 0.06]) were associated with a longer time to relapse (when adjusted for age, disease duration, and cytogenetic risk). 5 patients were alive (1 of 4 in remission, 1 unknown) at the time of analysis. The median survival after relapse was 0.72 (range 0.01–5.81) years. Age > 50 years (HR = 0.41 [0.21–0.80, p = 0.001]) and time from HCT to relapse > 3 years (HR = 0.2 [0.09–0.46, p < 0.001]) were associated with better survival after relapse. Patients who relapsed at > 3 years (HR = 0.24 [0.09–0.63, p = 0.004]) and patients who received a second HCT (HR = 0.34 [0.12–0.94, p = 0.039]) had increased survival after relapse (adjusted for age, year, and cytogenetic risk at relapse). Cytogenetic risk at relapse was not significantly associated with survival after relapse.

Haploidentical Stem Cell Transplantation for the Treatment of Myelodysplastic Syndrome

Kunacheewa and colleagues (2020) stated that the use of allogeneic HSCT is recommended during the first CR of AML and high-risk MDS.  However, only 30 % of these cases have fully matched sibling donors (MSDs).  Alternatively, MUDs and haplo-identical (haplo) donors from first-degree relatives increase the access to transplantation, with some reported differences in outcomes.  The current systematic review and meta-analysis was conducted with the aim of summarizing the results of those studies to compare the efficacy and toxicity of MSD-HSCT and MUD-HSCT versus haplo-HSCT for patients with AML or MDS.  Articles published before September 15, 2018, were individually searched for in 2 data-bases (Medline and Embase) by 2 investigators.  The effect estimates and 95 % CIs from each eligible study were combined using the Mantel-Haenszel method.  A total of 14 studies met the eligibility criteria and were included in the meta-analysis.  The OS rates were not significantly different between the groups, with pooled odds ratios (ORs) of the chance of surviving at the end of the study when comparing haplo-HSCT to MSD-HSCT and comparing haplo-HSCT to MUD-HSCT of 0.85 (95 % CI: 0.70 to 1.04; I2 = 0 %) and 1.12 (95 % CI: 0.89 to 1.41; I2 = 33 %), respectively.  The pooled analyses of other outcomes also showed comparable results, except for the higher grade 2 to 4 aGVHD for patients who received haplo-HSCT than those who received MSD-HSCT, and the better GVHD-free, relapse-free survival and the lower cGVHD than the patients in the MUD-HSCT group.  The authors concluded that these observations suggested that haplo-HSCT is a reasonable alternative with comparable efficacy if MSD-HSCT and MUD-HSCT could not be performed.  Nonetheless, the primary studies included in this meta-analysis were observational in nature, and randomized-controlled trials (RCTs) are still needed to confirm the efficacy of haplo-HSCT.

The authors stated that this systematic review and meta-analysis had several drawbacks.  The most importation limitation was the observational nature of the included studies, as none was a RCT.  Thus, it was very likely that the baseline characteristics of the patients in each group were not perfectly similar, and the observed results could therefore be skewed by the unequal distribution of confounders and/or effect modifiers.  The between-study heterogeneity was also high in several pooled analyses, which was likely to be due to the difference in background populations, follow-up protocols, conditioning regimens, GVHD prophylaxis regimens, and stem cell sources across the included studies.  Furthermore, when time to transplant was taken into account, patients who received haplo-HSCT might have access to treatment more rapidly than those using other donors' sources.  That might affect the outcome of transplantation.  These researchers found that some of the included studies reported no significant difference in the duration from diagnosis to the date of transplantation between the 2 groups of patients.  However, the rest of the studies did not provide these data; thus, these investigators could not completely conclude that waiting time prior to HSCT was not significantly different between both groups.

Use of Hypomethylating Agents Before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome

Qin et al (2019) noted that the use of hypo-methylating agents (HMAs) prior to HSCT in patients with MDS was still controversial.  In a systematic review and meta-analysis, these researchers examined the impact of hypomethylation agents (HMAs) prior to HSCT, with a special focus on long-term outcome.  Databases, including PubMed, Embase Ovid, and the Cochrane Library, were searched for studies published up to November 4, 2018; OS was selected as the primary endpoint, and RFS was the secondary endpoint.  A total of 6 cohort studies were included in the final meta-analysis.  The findings showed that the outcome of patients with MDS using HMAs prior to HSCT was similar compared to those who did not with OS (HR = 0.81, 95 % CI: 0.63 to 1.04, p = 0.104) and RFS (HR = 0.96, 95 % CI: 0.72 to 1.26, p = 0.749).  The pooled HR of OS in the older patients was 0.75 (95 % CI: 0.57 to 0.98, p = 0.035).  No evidence showed that patients with MDS would benefit from using HMAs before HSCT in long-term survival (OS and RFS) compared to chemotherapy or best supportive care (BSC), although older patients were more likely to benefit from pre-transplantation HMAs treatment in terms of long-term survival.  The authors concluded that these observations await validation by prospective studies with larger sample size and randomized-controlled design.  Furthermore, future studies to clarify if older patients who are candidates for HSCT could benefit from this bridging treatment would be of great interest.

Wang and colleagues (2021a) noted that allo-HSCT is the only curative therapy for advanced MDS; however, the value of pre-transplant cytoreduction remains debatable.  In a retrospective study, these researchers compared the outcomes of upfront transplantation and pre-transplant cytoreduction.  Of 69 patients, 39 received upfront allo-HSCT and 30 received pre-transplant cytoreduction, including chemotherapy (n = 16), HMAs (n = 6), and HMAs with chemotherapy (n = 8).  The upfront group achieved similar OS and a trend of better progression-free survival (PFS) from diagnosis compared with the cytoreduction group (3-year PFS, 64.0 % versus 44.4 %, p = 0.076).  Post-transplant outcomes were comparable between the 2 groups in terms of OS, RFS, cumulative incidence of relapse (CIR), and NRM.  In patients with greater than or equal to 2 mutations, the upfront group achieved better OS and PFS (3-year OS, 100.0 % versus 68.6 %, p = 0.044; 3-year PFS: 92.3 % versus 43.9 %, p = 0.016) than the cytoreduction group.  Patients achieving remission in the cytoreduction group had outcomes similar to the upfront group, but those without remission before transplantation had a significantly worse post-transplant OS (3-year OS, 46.7 % versus 75.7 %, p = 0.038).  Patients with pre-transplant HMAs had better PFS than those with chemotherapy or HMAs plus chemotherapy (p < 0.05).  The authors concluded that compared with pre-transplant cytoreduction, upfront allo-HSCT might provide more benefit to some patients with advanced MDS if there are suitable donors; HMAs would be a good alternative during the donor search.

Wang and colleagues (2021b) stated that the value of pre-transplant cytoreductive therapy for patients with MDS is controversial.  In a meta-analysis, these investigators examined the effects of cytoreduction before transplantation.  PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies comparing post-transplant outcomes in MDS patients receiving different pre-transplant therapy.  Pooled HRs and 95 % CIs were calculated.  A total of 18 studies were included.  Post-transplant outcomes were similar for MDS patients receiving pre-transplant cytoreductive therapy and upfront transplantation in terms of OS (HR, 0.92; 95 % CI: 0.79 to 1.07), RFS (HR, 1.18; 95 % CI: 0.94 to 1.47), CIR (HR, 1.08; 95 % CI: 0.88 to 1.33), and NRM (HR, 0.93; 95 % CI: 0.74 to 1.18).  Pre-transplant HMAs and chemotherapy were not different regarding post-transplant OS, RFS, CIR, and NRM.  Achieving CR before transplantation was associated with increased RFS (HR, 0.80; 95 % CI: 0.63 to 1.00) and decreased NRM (HR, 0.53; 95 % CI: 0.32 to 0.90) when compared with upfront transplantation.  The authors concluded that timely transplantation is of great value for MDS patients.  Suitable pre-transplant cytoreduction could be used during the search for donors.

Liu and associates (2021) noted that HMAs are effective therapies for patients with MDS; however, allo-HSCT is the only way to cure MDS.  According to the current literature, it is difficult to confirm if HMAs bridging therapy is beneficial for MDS patients receiving allo-HSCT.  These researchers examined the effect of HMAs on long-term survival of MDS patients.  Databases, including PubMed, Embase Ovid, and the Cochrane Library, were searched for studies published up to January 10, 2021.  Patients who accepted HMAs bridging to allo-HSCT were defined as experimental group, while patients who received the BSC before allo-HSCT were the control group; the primary endpoint was OS.  A total of 7 studies were included in the final analysis.  The final results showed no OS differences between patients accepted HMAs before allo-HSCT and those received BSC (HR = 0.86, 95 % CI: 0.64 to 1.15, p = 0.32), indicating that MDS patients' long-term survival did not benefit from HMAs bridging therapy before allo-HSCT.  The authors concluded that this conclusion needs to be validated by large, prospective RCTs, which have guiding significance for the treatment of MDS patients.

Maintenance with Hypo-Methylating Agents After Allogeneic Stem Cell Transplantation in Myelodysplastic Syndrome

Bewersdorf et al (2021) noted that disease relapse remains the major cause of death among patients with AML and myelodysplastic syndrome (MDS) who receive an allo-HCT.  Maintenance treatment with FLT3 inhibitors and HMA has been studied in various clinical trials with mixed results.  In a systematic review and meta-analysis, these investigators examined the available evidence on the safety and effectiveness of FLT3 inhibitors and HMA for maintenance therapy following allo-HCT in AML and MDS.  They searched Cochrane Library, Google Scholar, Ovid Medline, Ovid Embase, PubMed, Scopus, and Web of Science Core Collection from inception to March 2021 for studies on maintenance therapies following allo-HCT in AML and MDS.  Studies were excluded if they were reviews, commentaries, case series with less than 5 patients, or basic research articles, not published in English, not on post-allo-HCT maintenance with FLT3 inhibitors or HMA in AML or MDS, or if they were clinical trials without published results or duplicate publications from the same patient cohort.  Studies with insufficient reporting of the primary endpoint (2-year OS) and studies using FLT3 inhibitors or HMA for pre-emptive treatment of imminent relapse based on positive measurable residual disease testing were excluded.  Random-effects models were used to pool response rates for the primary outcome of 2-year OS; HR for death and relapse were calculated for studies that included a control group.  Rates of RFS, NRM, as well as aGVHD and cGVHD were studied as secondary endpoints.  Downs and Black checklist and risk of bias assessments were used to gauge the quality of individual studies.  The search strategy identified 5,559 studies; 21 studies with a total of 809 patients were included in the meta-analysis.  The 2-year OS rates were 81.7 % (95 % CI: 73.8 % to 87.7 %) and 65.7 % (95 % CI: 55.1 % to 74.9 %) among patients treated with FLT3 inhibitors and HMA, respectively.  In sensitivity analyses restricted to studies that included a control group, maintenance therapy with FLT3 inhibitors (HR for death = 0.41; 95 % CI: 0.26 to 0.62) or HMA (HR = 0.45; 95 % CI: 0.31 to 0.66) appeared superior to no maintenance therapy.  The 2-year RFS rates were 79.8 % (95 % CI: 75.0 % to 83.9 %) and 62.4 % (95 % CI: 50.6 % to 72.9 %) among patients treated with FLT3 inhibitors and HMA, respectively.  Rates of any grade aGVHD and cGVHD were 33.1 % (95 % CI: 25.4 % to 41.8%; grade 3/4: 16.5 %) and 42.5 % (95 % CI: 26.3 % to 60.4 %) among FLT3 inhibitor and 42.7 % (95 % CI: 33.5 % to 52.4 %; grade 3/4: 8.1 %) and 41.5 % (95 % CI: 32.0 % to 51.6 %) among HMA-treated patients, respectively.  The authors concluded that maintenance therapy with either FLT3 inhibitors or HMA following allo-HCT could lead to prolonged and improved OS and RFS with a favorable safety profile.  Additional studies are needed to define the optimal duration of treatment, the role of measurable residual disease status, and transplant characteristics in patient selection.

Kungwankiattichai et al (2022) stated that HMAs appear to have a range of properties favorable to post- allo-HCT maintenance in AML patients.  In a systematic review and meta-analysis, these investigators searched the Embase, Medline, and Cochrane Central Register of Controlled Trials databases to identify relevant studies published from inception to November 18, 2021.  These trials compared HMA maintenance to observation following allo-SCT for AML or MDS.  A total of 14 studies met the eligibility criteria.  The OS and RFS of the HMA maintenance group were superior to the observation group, with a pooled RR of 1.38 and 1.46, respectively.  Moreover, the cumulative incidence of relapse was significantly lower in those who received HMAs.  The HMA group also had lower NRM compared with the observation group.  Overall, the incidences of grades III to IV aGVHD and cGVHD did not differ in both groups.  However, when looking specifically at those receiving decitabine maintenance, the rate of cGVHD appeared to be lower compared with observation alone.  The authors concluded that the findings of this systematic review and meta-analysis showed that AML and MDS patients receiving HMA maintenance following allo-SCT had better outcomes with regards to OS, RFS, NRM, CIR as well as a reduced incidence of cGVHD.

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References