Hematopoietic Cell Transplantation for Myelofibrosis

Number: 0838

Table Of Contents

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

Policy

Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for myelofibrosis.

  1. Medical Necessity

    Aetna considers allogeneic (ablative and non-myeloablative) hematopoietic cell transplantation (HCT) medically necessary for individuals with myelofibrosis (MF) when any of the following criteria is met: 

    1. The individual is dependent on transfusions of red blood cells; or
    2. The individual is dependent on transfusions of platelets or has frequent infarctions; or
    3. The individual has an absolute neutrophil count less than 1000/mm3; or
    4. The individual is resistant to conservative therapy; or
    5. The individual has intermediate or high risk MF.

    Aetna considers a repeat allogeneic (ablative or non-myeloablative) HCT medically necessary for individuals with myelofibrosis and primary graft failure or who have relapsed.

  2. Experimental and Investigational

    Aetna considers the following interventions experimental and investigational because the effectiveness of these approaches has not been established:

    1. Mutational profiling (use of genetic biomarkers) for assessing prognosis following HCT for myelofibrosis
    2. Pre-HCT ruxolitinib for myelofibrosis
    3. Splenic irradiation before HCT for myelofibrosis
    4. Autologous hematopoietic cell transplantation for myelofibrosis
    5. Allogeneic stem cell transplantation combined with transfusion of mesenchymal stem cells for the treatment of myelofibrosis
    6. Artificial intelligence (machine learning and deep learning models) for risk stratification in myelofibrosis
    7. Splenic irradiation before allogeneic transplant conditioning for myelofibrosis. 

  3. Related Policies

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

CPT codes covered if selection criteria are met :
38204 - 38205, 38207 - 38215, 38230, 38240, 38242 Bone marrow or stem cell services/procedures-allogenic [not covered for allogeneic stem cell transplantation combined with transfusion of mesenchymal stem cells]

CPT codes not covered for indications listed in the CPB:
Mutational profiling (use of genetic biomarkers) for prognosis following hematopoietic cell transplantation (HCT) for myelofibrosis, artificial intelligence for risk stratification in myelofibrosis, splenic irradiation - no specific code
38232 Bone marrow harvesting for transplantation; autologous
38241 Hematopoietic progenitor cell (HPC); autologous transplantation

Other HCPCS codes related to the CPB:

Ruxolitinib - no specific code:

ICD-10 codes covered if selection criteria are met:
D75.81 Myelofibrosis

Background

Primary MF is considered a chronic myeloproliferative disorder and is characterized by variable degrees of cytopenia, cytosis, bone marrow fibrosis, a leukoerythroblastic blood picture, and extramedullary hematopoiesis, which can result in hepatosplenomegaly (Cervantes et al, 2009). MF is a heterogeneous disease in that MF is an indolent disease in some patients, who may survive for decades, to an aggressive disease in others, with disabling symptoms, lowered quality of life and in some cases survival of less than a year (McLornan et al, 2012). MF can be either primary or secondary, and can develop in patients with polycythemia vera or essential thrombocythemia. The median age is in the seventh decade and approximately 70% of patients are positive for the Janus2 kinase mutation (Ballen, 2012).

There have been no available conventional drug therapies for MF which have been shown to prolong survival. Palliative agents include erythropoietin, androgens, immunomodulatory agents, interferons, cytoreductive therapies and non-pharmacologic approaches. The non-pharmacologic approaches include blood transfusion, splenic irradiation, and splenectomy. Allogeneic hematopoietic stem cell transplantation (SCT) is considered to be the only potentially curative therapy for MF (McLornan et al, 2012).

The American Society for Blood and Marrow Transplantation Guideline on the role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndrome states that” early SCT is recommended for patients with an International Prognostic Scoring System (IPSS) score of intermediate (INT) -2 (considered high risk) at diagnosis who have a suitable donor and meet the transplant center’s eligibility criteria, and for selected patients at low risk (IPSS score of INT-1) at diagnosis who have poor prognostic features not included in the IPSS (e.g. older age, refractory cytopenias) (Oliansky et al, 2009). The IPSS estimates survival from the time of diagnosis based on five risk factors : age > 65 years, hemoglobin < 100 g/l, leukocyte count > 25 x 109/l, circulating blasts ≥ 1%, and the presence of constitutional symptoms. Patients are then classified as low risk (score = 0), intermediate risk-1 (score = 1), intermediate risk-2 (score = 2), and high risk (score ≥ 2) (McLornan et al, 2012).

Cervantes et al (2009) studied 1054 patients at 7 centers who were diagnosed with primary MF. The purpose of this retrospective study was to develop a highly discriminative prognostic system. Variables selected for prognostic assessment were those previously shown to be of prognostic value in primary MF along with variables considered to be either clinically meaningful or potential confounders. Analysis using Cox proportional hazards modeling revealed identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 x 109/L, and circulating blast cells 1% or greater as predictors of shortened survival. Overall median survival was 69 months (95% confidence interval: 61-71).  Four risk groups with no overlap in their survival curves were identified, including 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2), or greater than or equal to 3 (high risk), with respective median survivals of 135, 95, 48, and 27 months (p < 0.001). Additionally, in 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival.

Kroger and colleagues (2009) noted that from 2002 to 2007, a total of 103 patients with primary myelofibrosis or post-essential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range of 32 to 68 years) were included in a prospective, multi-center phase-II clinical trial to examine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m(2))-based reduced-intensity conditioning (RIC) regimen followed by allogeneic stem cell transplantation (ASCT) from related (n = 33) or unrelated donors (n = 70). All but 2 patients (2 %) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versus-host disease (aGVHD) grade 2 to 4 occurred in 27 % and chronic GVHD (cGVHD) in 43 % of the patients. Cumulative incidence of non-relapse mortality (NRM) at 1 year was 16 % (95 % confidence interval [CI]: 9 % to 23 %) and significantly lower for patients with a completely matched donor (12 % versus 38 %; p = 0.003). The cumulative incidence of relapse at 3 years was 22 % (95 % CI: 13 % to 31 %) and was influenced by Lille risk profile (low, 14 %; intermediate, 22 %; and high, 34 %; p = 0.02). The estimated 5-year event-free survival (EFS) and overall survival (OS) was 51 % and 67 %, respectively. In a multi-variate analysis, age older than 55 years (hazard ratio [HR] = 2.70; p = 0.02) and human leukocyte antigen (HLA)-mismatched donor (HR = 3.04; p = 0.006) remained significant factors for survival.

Tefferi et al (2011a) noted that “current drug therapy in primary MF is neither curative or essential for survival. Similarly, it is not clear if the application of allogeneic SCT, with its attendant risk of death or chronic morbidity from graft-versus-host disease, has had a favorable or unfavorable net effect. Therefore, one must first determine whether a particular patient needs any form of therapy at all and , if so, carefully select the treatment strategy with the best chance of inducing disease control without compromising life expectancy.” Tefferi et al (2011b) reported that the presence of fibrosis, JAK2/MPL mutation or +9/13q- cytogenic abnormality is supportive but not essential for diagnosis, and that diagnosis is based on bone marrow morphology.  The authors state that observation alone is adequate for asymptomatic low/intermediate-1 risk disease; allogeneic SCT or experimental drug therapy is reasonable for symptomatic intermediate-1 risk disease. 

Alchalby et al (2012) evaluated 150 homogeneously treated MF patients who underwent reduced-intensity allogeneic SCT and developed a risk score for overall survival. The authors’ prognostic scoring system compared to the Lille scoring system and correlated significantly with overall survival but discriminated poorly between the intermediate and high-risk groups. The authors concluded that a simple model which includes age, JAK2 V617F-status, and constitutional symptoms can clearly separate distinct risk groups.  The authors further noted that such a model can be used in addition to the Lille model to predict overall survival after reduced-intensity allogeneic SCT. 

Scott et al (2012) conducted a study to evaluate a Dynamic International Prognostic Scoring System (DIPSS) risk categorization. They evaluated the DIPSS in 170 MF patients aged 12 to 78 years who received SCT from related (n = 86) or unrelated (n = 84) donors. The investigators determined that 21 patients had low-risk disease, 48 had intermediate-1, 50 had intermediate-2, and 51 had high-risk disease. Additionally, they reported five-year incidence of relapse, relapse-free survival, overall survival, and nonrelapse mortality for all patients were 10%, 57%, 57%, and 34%, respectively. They concluded that SCT was curative for a large proportion of patients with MF, and post-SCT success was dependent on pre-SCT DIPSS classification.

In a recent review of allogeneic stem cell transplantation for MF, McLornan et al (2012) concluded that transplant-eligible MF patients with intermediate-2 and high-risk disease should be considered for SCT. Additionally, patients with transfusion dependency or an unfavorable karyotype should also be considered for SCT. The authors suggested a myeloablative conditioned approach in those greater than 45 years of age, and acknowledged that some patients between 45 and 50 years of age with low HCT-CI scores may well also be suitable for a myeloablative conditioned SCT. They further suggested that a reduced-intensity conditioning regimen be considered for those over the age of 45 years and that patients older than 65 years should not be definitively excluded from potential SCT on age criteria alone, but rather that “a frank discussion with the patient regarding the association of older age and, in general, an adverse post-SCT outcome should occur in addition to a detailed risk assessment".

An UpToDate review on “Prognosis and treatment of primary myelofibrosis” (Tefferi, 2013) provides the following recommendations:

  • For younger patients (i.e., age less than 45 years) at intermediate-2 or high risk according to the DIPSS [Dynamic International Prognostic Scoring System] Plus scoring system, we suggest that the patient be considered for hematopoietic cell transplantation (HCT) shortly after diagnosis (Grade 2B).  We prefer conventional intensity conditioning for those less than 45 years of age and reduced-intensity conditioning for those 45 to 65 years of age.
  • For DIPSS Plus low-risk patients, who might live 10 to 15 years with supportive treatment alone, but might have a transplant-related mortality of at least 8 percent, the answer is not yet clear.  Until further information is available, we suggest against the use of HCT for this group of patients (Grade 2C).

In an update on the diagnosis, risk-stratification, and management of primary myelofibrosis (PMF), Tefferi et al (2014a) stated that PMF is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extra-medullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.  Diagnosis is based on bone marrow morphology.  The presence of JAK2, CALR, or MPL mutation is supportive but not essential for diagnosis; approximately 90 % of patients carry 1 of these mutations and 10 % are "triple-negative".  None of these mutations is specific to PMF and is also seen in essential thrombocythemia (ET).  Pre-fibrotic PMF mimics ET in its presentation and the distinction, enabled by careful bone marrow morphological examination, is prognostically relevant.  Differential diagnosis also includes chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.  The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses 8 predictors of inferior survival: age greater than 65 years, hemoglobin less than 10 g/dL, leukocytes greater than 25 × 10(9) /L, circulating blasts greater than or equal to 1 %, constitutional symptoms, red cell transfusion dependency, platelet count less than 100 × 10(9) /L, and unfavorable karyotype (i.e., complex karyotype or sole or 2 abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement).  The presence of 0, 1, "2 or 3", and greater than or equal to 4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively.  High risk disease is also defined by CALR(-) /ASXL1(+) mutational status.  Observation alone is adequate for asymptomatic low/intermediate-1 risk disease, especially with CALR(+) /ASXL1(-) mutational status.  Stem cell transplant is considered for DIPSS-plus high-risk disease or any risk disease with CALR(-) /ASXL1(+) mutational status.  Investigational drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease.  Splenectomy is considered for drug-refractory splenomegaly.  Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain. 

About 5 to 18 % of patients with myelofibrosis with myeloid metaplasia (MMM) who undergo allogeneic myeloablative transplantation will relapse after 3 years (Tanvetyanon and Stiff, 2004).  Relapse carries a high mortality: 50 % of the patients will die within 1 year.  Increased age, impaired performance status, and reduced organ reserve often hamper further attempt at myeloablative chemotherapy.

Klyuchnikov et al (2012) reported the results of a second hematopoietic stem cell transplantation (HSCT) as salvage therapy in myelofibrosis patients who have relapsed or experienced graft rejection.  A total of 30 myelofibrosis patients (21 males, 9 females) with relapse (n = 27) or graft-rejection (n = 3) after dose-reduced allografting underwent a salvage strategy including donor lymphocyte infusions (DLIs) and/or second allogeneic hematopoietic stem cell transplantation (HSCT); 26 patients received a median number of 3 (range of 1 to 5) DLIs in a dose-escalated mode starting with a median dose of 1.2 × 10(6) (range of 0.003 to 8 × 10(6) ) up to median dose of 40 × 10(6) T-cells/kg (range of 10 to 130 × 10(6) ); 10/26 patients (39 %) achieved complete response (CR) to DLIs.  Acute (grade II to IV) and chronic graft-versus-host (GVHD) disease occurred in 12 % and 36 % cases; 13 non-responders to DLI and 4 patients who did not receive DLI due to graft-rejection or acute transformation of the blast phase underwent a second allogeneic HSCT from alternative (n = 15) or the same (n = 2) donor.  One patient (6 %) experienced primary graft-failure and died.  Acute (grade II to IV) and chronic GVHD were observed in 47 % and 46 % of patients.  Overall responses after second HSCT were seen in 12/15 patients (80 %: CR: n = 9, partial response: n = 3).  The 1-year cumulative incidence of non-relapse mortality for recipients of a second allograft was 6 %, and the cumulative incidence of relapse was 24 %.  After a median follow-up of 27 months, the 2-year overall survival and progression-free survival for all 30 patients was 70 % and 67 %, respectively.  The investigators concluded that their 2-step strategy, including DLI and second HSCT for non-responding or ineligible patients, is an effective and well-tolerated salvage approach for patients relapsing after reduced-intensity allograft after myelofibrosis.

Mutational Profiling (Use of Genetic Biomarkers) for Prognosis Following Hematopoietic Cell Transplantation

Kroger and colleagues (2017) stated that molecular genetics may influence outcome for patients with MF.  These researchers examined the impact of molecular genetics on outcome following allogeneic stem cell transplantation (ASCT).  They screened 169 patients with PMF (n = 110), post-essential thrombocythemia/polycythemia vera MF (n = 46), and MFs in transformation (n = 13) for mutations in 16 frequently mutated genes.  The most frequent mutation was JAK2V617F (n = 101), followed by ASXL1 (n = 49), calreticulin (n = 34), SRSF2 (n = 16), TET2 (n = 10), U2AF1 (n = 11), EZH2 (n = 7), MPL (n = 6), IDH2 (n = 5), IDH1 (n = 4), and CBL (n = 1).  The cumulative incidence of non-relapse mortality (NRM) at 1 year was 21 % and of relapse at 5 years 25 %.  The 5-year progression-free survival (PFS) and overall survival (OS) were 48 % and 56 %, respectively.  In a multivariate analysis CALR mutation was an independent factor for lower NRM (hazard ratio [HR], 0.415; p = 0.05), improved PFS (HR, 0.393; p = 0.01), and OS (HR, 0.448; p = 0.03).  ASXL1 and IDH2 mutations were independent risk factors for lower PFS (HR, 1.53 [p = 0.008], and HR, 5.451 [p = 0.002], respectively), whereas no impact was observed for "triple negative" patients.  The authors concluded that molecular genetics, especially CALR, IDH2, and ASXL1 mutations, may thus be useful to predict outcome independently from known clinical risk factors following ASCT for myelofibrosis.

Salit and Deeg (2018) noted that the prognosis of myeloproliferative neoplasms, including PMF, polycythemia vera, and essential thrombocythemia varies considerably, between these disorders as well as within each diagnosis.  Molecular studies have identified "driver mutations" in JAK2, MPL1, and CALR and additional somatic DNA mutations, including ASXL1, EZH2, IDH1/2, and SRSF2, that affect prognosis differentially.  Patients with mutations in CALR (type1) had a better outlook than patients with mutations in JAK2 or MPL, whereas patients without any of the driver mutations (triple-negative) had the shortest life expectancy.  Mutations in ASXL1, EZH2, and SRSF2 may be associated with shortened survival, and IDH mutations carried a higher risk of leukemic transformation.  The combination and number of mutations were more important than a given single mutation.  Mutations also appeared to impact the outcome of HCT, currently the only treatment with curative potential.  Based on available data, the best post-HCT outcome was observed with CALR mutations.  Triple negativity had a negative impact.  The data on JAK2 are controversial.  Mutations in ASXL1 or IDH1/2 reduced the probability of PFS following HCT, although the impact of ASXL1 differed between patients with PMF and secondary MF.  Although it is not clear to what extent HCT can overcome the risks associated with a given mutational pattern, at present, early HCT should be considered in triple-negative patients and patients with PMF who harbored mutations in ASXL1.  Mutations in EZH2, SRSF2, or IDH, particularly if combined with other mutations, should also lead to consideration of HCT.  The authors concluded that further studies are needed to validate the present observations and determine the impact of additional mutations that have been identified.

Tamari and associates (2019) stated that mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with MF.  However, there are limited data regarding the prognostic utility of genetic profiling in MF patients undergoing ASCT.  These researchers carried out high-throughput sequencing of 585 genes on pre-transplant samples from 101 patients with MF who underwent ASCT and evaluated the association of mutations and clinical variables with transplantation outcomes; OS at 5 years post-transplantation was 52 %, and relapse-free survival (RFS) was 51.1 % for this cohort; NRM accounted for most deaths.  Patient's age, donor's age, donor type, and DIPSS score at diagnosis did not predict for outcomes.  Mutations known to be associated with increased risk of disease progression, such as ASXL1, SRSF2, IDH1/2, EZH2, and TP53, did not impact OS or RFS.  The presence of U2AF1 (p = 0.007) or DNMT3A (p = 0.034) mutations was associated with worse OS.  A Mutation-Enhanced International Prognostic Scoring System 70 score was available for 80 patients (79 %), and there were no differences in outcomes between patients with high-risk scores and those with intermediate- and low-risk scores.  Collectively, these data identified mutational predictors of outcome in MF patients undergoing ASCT.  The authors concluded that these genetic biomarkers in conjunction with clinical variables may have important utility in guiding transplantation decision-making.

Pre-Hematopoietic Cell Transplant Ruxolitinib

Salit and associates (2020) stated that ruxolitinib (Rux), a Jak1/2 inhibitor, results in reduced spleen size and improvement in constitutional symptoms in the majority of patients with MF.  Thus, Rux, when given prior to HCT in patients with MF was hypothesized to improve engraftment, decrease incidence and severity of GVHD, and lower NRM.  In a phase-II clinical trial, these researchers examined the effects of pre-HCT Rux on post-HCT outcomes in patients with MF.  The primary end-point was 2-year OS.  To-date, a total of 28 patients (median age of 56 years) have been transplanted.  The median time on Rux pre-HCT was 7 months; 23 patients received myeloablative and 5 reduced intensity conditioning (RIC).  Donors included 14 HLA-matched siblings, 11 matched unrelated, 1 allele mismatched unrelated, and 3 umbilical cord blood.  There have been no episodes of cytokine release syndrome (CRS) and all patients achieved sustained engraftment; 2 patients died from NRM and 2 patients relapsed.  With a median follow-up of 13 months, OS was 93 % (95 % confidence interval [CI]: 0.73 to 0.98) at 1 year and 86 % (95 % CI: 0.61 to 0.96) at 2 years post-HCT.  The authors concluded that the findings of this study demonstrated that pre-HCT Rux was well-tolerated and suggested that pre-HCT Rux may improve post-HCT outcome.

In a 2-stage Simon phase-II clinical trial, Gupta and colleagues (2019) examined the feasibility of Rux therapy followed by a RIC regimen for patients with MF undergoing transplantation.  The objectives were to decrease the incidence of graft failure (GF) and NRM compared with data from the previous Myeloproliferative Disorders Research Consortium 101 Study.  The plan was to enroll 11 patients each in related donor (RD) and unrelated donor (URD) arms, with trial termination if greater than or equal to 3 failures (GF or death by day +100 post-transplant) occurred in the RD arm or greater than or equal to 6 failures occurred in the URD.  A total of 21 patients were enrolled, including 7 in the RD-arm and 14 in the URD-arm.  The RD-arm did not meet the pre-determined criteria for proceeding to stage II.  Although the URD-arm met the criteria for stage II, the study was terminated owing to poor accrual and a significant number of failures.  In all 19 transplant recipients, Rux was tapered successfully without significant side effects, and 9 patients (47 %) had a significant decrease in symptom burden.  The cumulative incidences of GF, NRM, acute GVHD, and chronic GVHD at 24 months were 16 %, 28 %, 64 %, and 76 %, respectively.  On an intention-to-treat (ITT) basis, the 2-year OS was 61 % for the RD-arm and 70 % for the URD-arm.  The authors concluded that Rux can be integrated as pre-transplantation treatment for patients with MF, and a tapering strategy before transplantation was safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant.

Splenic Irradiation Before Allogeneic Stem Cell Transplantation

Helbig and colleagues (2019) noted that splenectomy before ASCT for patients with MF remains a matter of debate, and conflicting results have been reported to-date.  The procedure appeared to fasten post-transplant hematological recovery, but it did not have an impact on survival.  The role of pre-transplant splenic irradiation (SI) is much more difficult to evaluate.  In this study, a total of 44 patients (25 males and 19 females) with MF at median age of 49 years at diagnosis (range of 14 to 67) underwent ASCT.  The post-transplant outcome was compared between irradiated and non-irradiated patients; 11 patients received irradiation before transplantation.  Median dose of radiation was 1,000 cGy (range of 600 to 2,400).  There was no difference in median time to engraftment between patients with and without previous radiotherapy.  Acute and chronic GVHD occurred in 47 % and 36 % of patients, respectively.  There was no difference in GVHD incidence between groups; 8 patients relapsed / progressed in irradiated group versus 17 in the non-irradiated group (70 % versus 51 %; p = 0.3).  Transformation to acute myeloid leukemia (AML) was observed in 3 patients: 2 in irradiated and 1 in non-irradiated group.  A total of 22 patients died with no statistical difference in death rate between irradiated and non-irradiated subjects.  The probability of OS following ASCT for the entire cohort at 2 years was 54 % (72 % for irradiated and 48 % for non-irradiated patients; p = 0.25).  The authors concluded that splenic irradiation prior to ASCT for myelofibrosis had no beneficial effect on post-transplant outcome and should not be routinely recommended.

Allogeneic Hematopoietic Stem Cell Transplantation with Fludarabine, Busulfan, and Thiotepa Conditioning

Shouval and colleagues (2020) stated that ASCT is a curative therapy for myelofibrosis; however, the optimal conditioning regimen has not been well-defined.  These researchers retrospectively compared transplantation outcomes in patients with myelofibrosis (n = 67) conditioned with myeloablative (MAC, 36 %) and RIC (46 %) regimens, and more recently with the combination of thiotepa, busulfan, and fludarabine (TBF, 18 %).  Patients were transplanted from HLA-matched sibling (n = 26) or unrelated donors (n = 41) between the years 2003 and 2018.  The median follow-up was 2.9 years for all patients but shorter in the TBF group (1.1 years).  The probability of 3-year PFS was 43 %.  At 1 year, the rate of PFS was 80 %, 54 %, and 45 % with TBF, MAC, and RIC, respectively (p = 0.031).  In a multi-vvariable model, there was a greater risk for death with MAC (HR 12.26, p = 0.026) and lower PFS with both MAC (HR 7.78, p = 0.017) and RIC (HR 5.43, p = 0.027) compared with TBF.  Relapse was higher with RIC (HR 8.20, p = 0.043) while NRM was increased with MAC (HR 9.63 p = 0.049).  These investigators stated that these findings indicated that TBF is a promising preparative regimen in myelofibrosis patients transplanted from matched sibling or unrelated donors, and should be further examined.

Allogeneic Hematopoietic Cell Transplantation in Older Myelofibrosis Patients

Hernandez-Boluda and colleagues (2021) stated that allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly used in older myelofibrosis (MF) patients; however, its risk/benefit ratio compared to non-transplant approaches has not been examined in this population.  These researchers analyzed the outcomes of allo-HCT in 556 MF patients aged greater than or equal to 65 years from the European Group for Blood and Marrow Transplantation (EBMT) registry, and determined the excess mortality over the matched general population of MF patients greater than or equal to 65 years managed with allo-HCT (n = 556) or conventional drug treatment (n = 176).  The non-transplant cohort included patients with intermediate-2 or high risk DIPSS from the Spanish Myelofibrosis Registry.  After a median follow-up of 3.4 years, the estimated 5-year survival rate, NRM, and relapse incidence after transplantation was 40 %, 37 %, and 25 %, respectively.  Busulfan-based conditioning was associated with decreased mortality (HR: 0.7, 95 % CI: 0.5 to 0.9) whereas the recipient CMV+/donor CMV- combination (HR: 1.7, 95 % CI: 1.2 to 2.4) and the JAK2 mutated genotype (HR: 1.9, 95 % CI: 1.1 to 3.5) predicted higher mortality.  Busulfan-based conditioning correlated with improved survival due to less NRM, despite its higher relapse rate when compared with melphalan-based regimens.  Excess mortality was higher in transplanted patients than in the non-HCT cohort in the 1st year of follow-up (HR: 1.93, 95 % CI: 1.13 to 2.80), whereas the opposite occurred between the 4th and 8th follow-up years (HR: 0.31, 95 % CI: 0.18 to 0.53).  the authors concluded that comparing the excess mortality of the 2 treatments, male patients appeared to benefit more than females from allo-HCT, primarily due to their worse prognosis with non-transplant approaches.  These researchers stated that these findings could potentially enhance counseling and treatment decision-making in elderly transplant-eligible MF patients.

Allogeneic Stem Cell Transplantation Combined with Transfusion of Mesenchymal Stem Cells for the Treatment of Myelofibrosis

Li et al (2021) stated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving approach for severe hematological conditions; however, its outcomes need further improvement, and co-infusion of mesenchymal stem cells (MSCs) may show promise.  While a growing body of research on this subject exists, the results of different trials were conflicting.  In a systematic review and meta-analysis, these researchers examined the safety and effectiveness of MSC co-transplantation in allo-HSCT.  They searched studies comparing MSC co-transplantation in allo-HSCT with allo-HSCT alone in 6 medical databases from inception to June 10, 2020.  The primary outcomes were engraftment as well as aGVHD and cGVHD.  Other outcomes included OS, relapse rate, NRM, and immune reconstitution.  Information was independently extracted by 2investigators; and methodological quality was evaluated using the Cochrane Collaboration tool.  Meta-analysis was carried out using RevMan 5.4.  A total of 6 randomized controlled trials (RCTs) and 13 non-RCTs (nRCTs) were included.  MSC co-infusion resulted in shorter times to neutrophil engraftment (RCTs: standardized mean difference (SMD) - 1.20, p = 0.04; nRCTs: SMD - 0.54, p = 0.04) and platelet engraftment (RCTs: SMD - 0.60, p = 0.04; nRCTs: SMD - 0.70, p = 0.01), a lower risk of cGVHD (RCTs: risk ratio (RR) 0.53, p = 0.01; nRCTs: RR 0.50, p < 0.01), and a slightly positive trend towards reducing the risk of aGVHD and NRM, without affecting relapse rate and OS.  Subgroup analyses revealed that when MSCs were co-transplanted, children and adolescents, and patients receiving human leukocyte antigen (HLA)-non-identical HSCT showed improvements in engraftment and incidence of GVHD and NRM; adults and patients who received HLA-identical HSCT had lower cGVHD; patients with malignancies exhibited improvements in GVHD and NRM incidence; and patients with non-malignancies experienced accelerated engraftment.  Notably, a reduced OS was observed in patients with hematological malignancies undergoing HLA-identical HSCT.  The authors concluded that the findings of this study supported the use of MSCs co-transplanted with HLA-non-identical HSCT in children and young individuals.  Since the effects of MSCs on blood malignancies are not well understood, these investigators did not recommend the use of MSCs co-transplanted with HLA-identical HSCT in adult patients with hematological malignancies based on the currently available data.  These researchers noted that in this meta-analysis, the number of studies conducted on patients with hematological malignancies undergoing HLA-identical HSCT was limited; therefore, additional in-depth assessments of the safety and effectiveness of MSC co-transplantation in this population are recommended to avoid harming patients.

The authors stated that this study had several drawbacks.  First, heterogeneity across studies, including the types and stages of diseases, sources and dosage of HSCs and MSCs, HLA matching, definitions of outcomes, varying follow-up times, and study designs, was notable, although these investigators carried out subgroup and sensitivity analyses to attempt to resolve the heterogeneity.  Furthermore, in the subgroups of non-malignant disorders and HLA-identical matching, no more than 3 trials were included in each meta-analysis.  Second, publication bias was possible because of the 4 trials that were completed but these researchers failed to find any related publications.  Third, these investigators restricted the language of the literature search to only Chinese and English, which may have resulted in a failure to retrieve some potentially relevant studies.  Fourth, 3 trials that were published in the form of abstracts in poster sessions, did not provide sufficient information to fully evaluate the source of the bias.  Fifth, the limitations of the I2 test must be considered.  Although most of the I2 test scores were less than 50 %, the I2 values were likely to be under-estimated, especially if a limited number of trials or a few events were evaluated in a meta-analysis

Wang et al (2022) noted that allogeneic stem cell transplantation (allo-SCT) remains the only effective curative treatment for primary myelofibrosis.  Use and effectiveness of allo-SCT are limited by lethal complications, including engraftment failure, as well as aGVHD and cGVHD).  Several clinical trials have examined the use of MSCs in allo-SCT to prevent hematopoietic stem cell (HSC) engraftment failure and control GVHD.  In a retrospective, multi-center study, these researchers examined clinical data of 17 patients with primary myelofibrosis who underwent allo-SCT combined with ex-vivo expanded MSC transfusion in 4 centers from February 2011 to December 2018.  All patients received myeloablative conditioning regimen.  The median number of transplanted nucleated cells (NCs) per kilogram body weight was 11.18 × 10(8)(range: of 2.63 to 16.75 × 10(8)), and the median number of CD34+ cells was 4.72 × 10(6) (range of 1.32 to 8.4 × 10(6)).  MSCs were transfused on the day of transplant or on day 7 after transplant.  The median MSC infusion number was 6.5 × 10(6) (range of 0.011 to 65 × 10(6)).  None of the patients experienced primary or secondary graft failure in the study.  The median time to neutrophil engraftment was 13 days (range of 11 to 22 days), and the median time to platelet engraftment was 21 days (range of 12 to 184 days).  The median follow-up time was 40.3 months (range of 1.8 to 127.8 months).  The estimated RFS at 5 years was 79.1 %, and OS at 5 years was 64.7 %.  Analysis showed that the cumulative incidence of aGVHD grade II to IV was 36 % (95 % CI: 8 % to 55 %) and that of grade III to IV was 26 % (95 % CI: 0 % to 45 %) at day 100.  The cumulative incidence of overall cGVHD at 2 years for the entire study population was 63 % (95 % CI: 26 % to 81 %).  The cumulative incidence of moderate-to-severe cGVHD at 2 years was 17 % (95 % CI: 0 % to 42 %); 7 patients died during the study, with 5 patients succumbing from non-relapse causes and 2 from disease relapse.  The authors concluded that the findings of the study indicated that allo-SCT combined with MSC transfusion may represent an effective therapeutic option for primary myelofibrosis.  Moreover, these researchers stated that prospective, controlled, large-scale studies are needed to validate the findings of this study.

The authors stated that drawbacks of this trial were those inherent to multi-center-based retrospective analyses; and included a lack of clarity for physician choice of time and dose of MSC infusion and heterogeneous data with GVHD prophylaxis and therapies associated with supportive care.  MSC dose varied greatly in previous literature.  Although it was reported that MSCs exerted an effect in a dose-dependent manner regarding engraftment promotion, the impact of MSC dose on engraftment still remains to be determined.  Furthermore, optimal timing of MSC infusion is inconclusive and may depend on the infusion purpose.

Bone Marrow Morphologic Evaluation for Predicting Response in Patients with Myelofibrosis Who Have Undergone Hematopoietic Stem Cell Transplantation

Khanlari et al (2022) noted that allo-HSCT is a curative option for patients with MF.  Bone marrow (BM) morphologic evaluation of MF following allo-HSCT is known to be challenging in this context because resolution of morphologic changes is a gradual process.  These researchers compared BM samples of patients with MF who underwent 1st allo-HSCT and achieved molecular remission by day 100 with BM samples of patients who continued to have persistent molecular evidence of disease following allo-HSCT.  The study group included 29 patients: 17 primary MF, 7 post-polycythemia vera (PV) MF, and 5 post-essential thrombocythemia (ET) MF.  In this cohort there were 18 JAK2 p.V617F, 8 CALR; 1 MPL, and 2 patients had concurrent JAK2 p.V617F and MPL mutations.  The control group included 5 patients with primary MF, 1 with post-PV MF, 1 with post-ET MF (5 JAK2 p.V617F; 2 CALR).  Following allo-HSCT, both groups showed reduction in BM cellularity and number of megakaryocytes.  The study cohort also less commonly had dense megakaryocyte clusters and endosteal located megakaryocytes and showed less fibrosis.  There was no statistical difference in BM cellularity, presence of erythroid islands, degree of osteosclerosis, or megakaryocyte number, size, nuclear lobation, presence of clusters or intra-sinusoidal location.  The authors concluded that following allo-HSCT at 100 days, morphologic evaluation of BM in patients with MF could not reliably predict persistence versus clearance of molecular evidence of MF.  Disappearance of BM MF, dense megakaryocyte clusters, and endosteal localization of megakaryocytes were suggestive of disease response.

Donor Lymphocyte Infusion and Molecular Monitoring for Relapsed Myelofibrosis After Hematopoietic Cell Transplantation

Gagelmann et al (2023) stated that HCT is a curative approach for myelofibrosis patients; however, relapse is a major cause of treatment failure.  These investigators examined the effect of donor lymphocyte infusion (DLI) in 37 patients with molecular (n = 17) or hematological relapse (n = 20) following HCT.  Patients received median of 2 (range of 1 to 5) cumulative DLI (total of 91 infusions).  Median starting dose was 1 × 10(6) cells/kg, escalated by half-log of greater than or equal to 6 weeks if no response nor GVHD occurred.  Median time to 1st DLI was 40 weeks for molecular relapse versus 145 weeks for hematological relapse.  Overall molecular complete response (mCR) at any time was 73 % (n = 27) and was significantly higher for initial molecular relapse (88 %) versus hematological relapse (60 %; p = 0.05).  The 6-year OS was 77 % versus 32 % (p = 0.03).  Acute GVHD 2-4 occurred in 22 % and half of the patients achieved mCR without any GVHD.  All patients who relapsed from mCR achieved after 1st DLI could be salvaged with subsequent DLI, showing long-term survival.  No 2nd HCT was needed for molecular relapse versus 6 for hematological relapse.  The authors concluded that this comprehensive and largest study to-date suggested molecular monitoring together with DLI as standard of care (SOC) and a crucial approach to achieve excellent outcomes in relapsed myelofibrosis.

Artificial Intelligence (Machine Learning and Deep Learning Models) for Risk Stratification

Mosquera-Orgueira et al (2023) noted that MF is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course.  Allo-HSCT remains the only curative therapy; however, its morbidity and mortality require careful candidate selection.  Thus, accurate disease risk prognostication is critical for treatment decision-making.  These researchers obtained registry data from patients diagnosed with MF in 60 Spanish institutions (n = 1,386).  These were randomly divided into a training set (80 %) and a test set (20 %).  A machine learning (ML) technique (random forest) was employed to model OS and leukemia-free survival (LFS) in the training set, and the results were validated in the test set.  These investigators derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703).  No improvement was obtained with the inclusion of MPN driver mutations in the model.  These researchers were unable to adequately evaluate the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients.  AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF.  The authors have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF.  The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.

The authors stated that the major drawbacks of this study derived from its registry-based nature.  Data quality depended on local physicians entering data at many different centers over a long follow-up period without centralized review.  These investigators have considered PMF patients with grades 0 to 1 and 2 to 3 bone marrow fibrosis to have pre-fibrotic and overt PMF, respectively; however, the diagnosis of pre-fibrotic PMF was only formally established in a minority of patients.  Thus, the performance of the AIPSS-MF in patients with pre-fibrotic PMF needs further validation.  Informative cytogenetic data was only available for 25 % of patients.  The registry included patients diagnosed from 2,000 onwards, and although most (82 %) of the series were annotated for MPN driver mutations, only a minority had next-generation sequencing (NGS) panel data evaluating additional somatic mutations.  Therefore, the authors were unable to adequately examine the potential benefit of including adverse cytogenetics or high-risk somatic mutations data in their prognostic model.  For the same reason, it was not possible to compare the predictive accuracy of their model with those that include genetic information, such as DIPSS plus, MIPSS70 or MIPSS70+ v2.0.  The performance of the model was assessed on a test set comprising 20 % of the patients in this registry; however, further external evaluation using data from other sources is needed.

Gedefaw et al (2023) stated that artificial intelligence (AI) is a rapidly evolving field of computer science that entails the development of computational programs that can mimic human intelligence.  In particular, ML and deep learning (DL) models have enabled the identification and grouping of patterns within data, leading to the development of AI systems that have been employed in various areas of hematology, including digital pathology, alpha thalassemia patient screening, cytogenetics, immunophenotyping, and sequencing.  These AI-assisted methods have shown promise in improving diagnostic accuracy and efficiency, identifying novel biomarkers, and predicting treatment outcomes.  However, limitations such as limited databases, lack of validation and standardization, systematic errors, and bias prevent AI from completely replacing manual diagnosis in hematology.  Furthermore, the processing of large amounts of patient data and personal information by AI poses potential data privacy issues, necessitating the development of regulations to examine AI systems and address ethical concerns in clinical AI systems.  The authors concluded that the use of AI in hematology diagnostics is on the rise, and it has the potential to facilitate hematology diagnosis by combining results from different diagnostic methods.  The use of AI in hematology diagnostics will aid in reducing the turnaround time, lowering diagnostic costs, and predicting disease outcomes.  However, it is important to note that AI cannot fully replace manual diagnosis due to its limitations, including limited databases, lack of validation and standardization, as well as the risk of systematic errors and bias.  In addition, the use of AI poses data privacy issues; thus, regulations on clinical AI systems, including evaluation of AI systems and regulations on ethical issues, are needed to protect user information and privacy.  To address the field’s current challenges, more research must be carried out.

Splenic Irradiation Before Allogeneic Transplant Conditioning

Campodonico et al (2023) stated that in the era of JAK inhibitors, allo-HSCT remains the only curative treatment for patients with MF.  Splenic irradiation (SI) may be used to reduce spleen size and related symptoms.  In a pilot study, these investigators carried out a retrospective analysis on 14 patients with MF who underwent allo-HSCT with SI from any donor source at the authors’ center between June 2016 and March 2021.  All patients received a conditioning backbone based on treosulfan and fludarabine, with post-transplant cyclophosphamide (PTCy) and sirolimus as GVHD prophylaxis.  Patients received SI with 10 Gy involved-field radiotherapy in five 2-Gy fractions over the course of a week before the beginning of conditioning.  At transplant all patients were transfusion-dependent and had splenomegaly (median bipolar diameter by ultrasound [US] of 20.75 cm).  A total of 12 patients had received ruxolitinib before transplantation.  Re-evaluation of spleen dimensions was available for 13 patients: median splenic bipolar diameter after at least 3 months from transplantation decreased by a median of 25 %.  With a median post-transplantation follow-up of 25 months, 6 patients remain in CR with full-donor chimerism, 3 patients died due to NRM.  Overall, 4 patients relapsed.  At last follow-up, 9 patients are currently alive and achieved transfusion-independence.  The authors concluded that in a small cohort of mostly ruxolitinib pre-treated patients, SI and treosulfan-based conditioning appeared a safe and effective tool to reduce spleen dimensions and ameliorate symptoms.  Moreover, these researchers stated that future prospective studies with adequate sample size are needed to further examine the safety and usefulness of this approach in MF.

References

The above policy is based on the following references:

  1. Alchalby H, Yunus DR, Zabelina T, et al. Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol. 2012;157(1):75-85.
  2. Ballen K. How to manage the transplant question in myelofibrosis. Blood Cancer J. 2012;2(3):e59.
  3. Bewersdorf JP, Sheth AH, Vetsa S, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis -- A systematic review and meta-analysis. Transplant Cell Ther. 2021;27(10):873.e1-873.e13.
  4. Campodonico E, Xue E, Piemontese S, et al. Splenic irradiation prior to allogeneic transplant conditioning in myelofibrosis: A pilot experience. Curr Res Transl Med. 2023 Jun 9 [Online ahead of print].
  5. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901.
  6. Daghia G, Zabelina T, Zeck G, et al. Allogeneic stem cell transplantation for myelofibrosis patients aged ≥ 65 years. Eur J Haematol. 2019;103(4):370-378.
  7. Gagelmann N, Wolschke C, Badbaran A, et al. Donor lymphocyte infusion and molecular monitoring for relapsed myelofibrosis after hematopoietic cell transplantation. Hemasphere. 2023;7(7):e921.
  8. Gedefaw L, Liu C-F, Ip RKL, et al. Artificial intelligence-assisted diagnostic cytology and genomic testing for hematologic disorders. Cells. 2023;12(13):1755.
  9. Gupta V, Kosiorek HE, Mead A, et al. Ruxolitinib therapy followed by reduced intensity conditioning for hematopoietic cell transplantation for myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study. Biol Blood Marrow Transplant. 2019;25(2):256-264.
  10. Helbig G, Wieczorkiewicz-Kabut A, Markiewicz M, et al. Splenic irradiation before allogeneic stem cell transplantation for myelofibrosis. Med Oncol. 2019;36(2):16.
  11. Hernandez-Boluda JC, Pereira A, Correa JG, et al. Prognostic risk models for transplant decision-making in myelofibrosis. Ann Hematol. 2018;97(5):813-820.
  12. Hernandez-Boluda J-C, Pereira A, Kroger N, et al. Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: A study of the chronic malignancies working party of EBMT and the Spanish Myelofibrosis Registry. Am J Hematol. 2021;96(10):1186-1194.
  13. Jain T, Kunze KL, Temkit M, et al. Comparison of reduced intensity conditioning regimens used in patients undergoing hematopoietic stem cell transplantation for myelofibrosis. Bone Marrow Transplant. 2019;54(2):204-211.
  14. Kamimura T, Yong C, Ito Y, et al. Clinical outcomes of allogeneic hematopoietic stem cell transplantation for adult primary myelofibrosis: Retrospective analysis by Fukuoka BMT group. Rinsho Ketsueki. 2012;53(3):323-328.
  15. Khanlari M, Wang X, Loghavi S, et al. Value and pitfalls of assessing bone marrow morphologic findings to predict response in patients with myelofibrosis who undergo hematopoietic stem cell transplantation. Ann Diagn Pathol. 2022;56:151860.
  16. Klyuchnikov E, Holler E, Bornhäuser M, et al. Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting. Br J Haematol. 2012;159(2):172-181.
  17. Konuma T, Kondo T, Kawata T, et al; Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation.  Hematopoietic cell transplantation for acute panmyelosis with myelofibrosis: A retrospective study in Japan. Biol Blood Marrow Transplant. 2019;25(1):e23-e27.
  18. Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: A prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(26):5264-5270.
  19. Kroger N, Panagiota V, Badbaran A, et al. Impact of molecular genetics on outcome in myelofibrosis patients after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23(7):1095-1101.
  20. Kroger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: A consensus process by an EBMT/ELN international working group. Leukemia. 2015;29(11):2126-2133.
  21. Lestang E, Peterlin P, Le Bris Y, et al. Is allogeneic stem cell transplantation for myelofibrosis still indicated at the time of molecular markers and JAK inhibitors era? Eur J Haematol. 2017;99(1):60-69.
  22. Li T, Luo C, Zhang J, et al. Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. Stem Cell Res Ther. 2021;12(1):246.
  23. Mannina D, Zabelina T, Wolschke C, et al. Reduced intensity allogeneic stem cell transplantation for younger patients with myelofibrosis. Br J Haematol. 2019;186(3):484-489.
  24. McLornan DP, Mead AJ, Jackson G, Harrison CN. Allogeneic stem cell transplantation for myelofibrosis in 2012. Br J Haematol. 2012;157(4):413-425.
  25. McLornan DP, Yakoub-Agha I, Robin M, et al. State-of-the-art review: Allogeneic stem cell transplantation for myelofibrosis in 2019. Haematologica. 2019;104(4):659-668.
  26. Mosquera-Orgueira A, Perez-Encinas M, Hernandez-Sanchez A, et al. Machine learning improves risk stratification in myelofibrosis: An analysis of the Spanish Registry of myelofibrosis. Hemasphere. 2022;7(1):e818.
  27. Murata M, Suzuki R, Nishida T, et al. Allogeneic hematopoietic stem cell transplantation for post-essential thrombocythemia and post-polycythemia vera myelofibrosis. Intern Med. 2020;59(16):1947-1956.
  28. Nabergoj M, Mauff K, Robin M, et al. Outcomes following second allogeneic haematopoietic cell transplantation in patients with myelofibrosis: A retrospective study of the Chronic Malignancies Working Party of EBMT. Bone Marrow Transplant. 2021;56(8):1944-1952.
  29. Oliansky DM, AntinJH, Bennett JM, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence based review. Biol Blood Marrow Transplant. 2009;15(2):137-172.
  30. Reilly JT, McMullin MF, Beer PA, et al, Writing group: British Committee for Standards in Haematology. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012;158(4):453-471.
  31. Robin M, Porcher R, Wolschke C, et al. Outcome after transplantation according to reduced-intensity conditioning regimen in patients undergoing transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2016;22(7):1206-1211.
  32. Salit RB, Deeg HJ. Transplant decisions in patients with myelofibrosis: Should mutations be the judge? Biol Blood Marrow Transplant. 2018r;24(4):649-658.
  33. Salit RB, Scott BL, Stevens EA, et al. Pre-hematopoietic cell transplant ruxolitinib in patients with primary and secondary myelofibrosis. Bone Marrow Transplant. 2020;55:70-76.
  34. Scott BL, Gooley TA, Sorror ML, et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood. 2012;119(11):2657-2664.
  35. Shouval R, Vega Y, Fein JA, et al. Allogeneic hematopoietic stem cell transplantation with fludarabine, busulfan, and thiotepa conditioning is associated with favorable outcomes in myelofibrosis. Bone Marrow Transplant. 2020;55(1):147-156.
  36. Sliwa T, Beham-Schmid C, Burgstaller S, et al. Austrian recommendations for the management of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis: An expert statement. Wien Klin Wochenschr. 2017;129(9-10):293-302.
  37. Soyer N, Celik F, Tombuloglu M, et al. Role of allogeneic stem cell transplant in the treatment of primary myelofibrosis. Exp Clin Transplant. 2019;17(1):93-96.
  38. Tamari R, Rapaport F, Zhang N, et al. Impact of high-molecular-risk mutations on transplantation outcomes in patients with myelofibrosis. Biol Blood Marrow Transplant. 2019;25(6):1142-1151.
  39. Tanvetyanon T, Stiff PJ. Second allogeneic transplantation using a reduced-intensity preparative regimen for relapsed myelofibrosis. Am J Hematol. 2004;77(2):204-205.
  40. Tefferi A. Primary myelofibrosis: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2011b;86(12):1017-1026.
  41. Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014a;89(9):915-925.
  42. Tefferi A. Prognosis and treatment of primary myelofibrosis. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed September 2013; August 2014b.
  43. Tefferi A. How I treat myelofibrosis. Blood. 2011a;117:3494-3504.
  44. Wang Q, Xu N, Wang Y, et al. Allogeneic stem cell transplantation combined with transfusion of mesenchymal stem cells in primary myelofibrosis: A multicenter retrospective study. Front Oncol. 2022;11:792142.
  45. Zeng X, Xuan L, Fan Z, et al. Allogeneic stem cell transplantation may overcome the adverse impact of myelofibrosis on the prognosis of myelodysplastic syndrome. Exp Hematol Oncol. 2021;10(1):44.