Stem Cell Transplantation For Myelofibrosis Research Articles

The application of JAK inhibitors in the peri-transplantation period of hematopoietic stem cell transplantation for myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with a poor prognosis, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in improving patients' symptoms, overall survival, and quality of life, and can be used as a bridging therapy to HSCT that increases the proportion of transplantable patients. However, the effect of this and similar drugs on HSCT outcomes is unknown, and the reports on their efficacy and safety in the peri-transplantation period vary widely in the published literature. This paper reviews clinical data related to the use of JAK inhibitors in the peri-implantation phase of hematopoietic stem cell transplantation for primary myelofibrosis and discusses their efficacy and safety.

Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.

We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings.

British Columbia Experience in Allogeneic Stem Cell Transplantation for Myelofibrosis with or without Pre-Transplant Ruxolitinib

Introduction Allogeneic stem cell transplantation (AlloHSCT) remains the only potentially curative treatment for myelofibrosis (MF). It confronts many challenges stemming from the older age of the typical patients and their age-related comorbidities, as well as disease-specific factors such as splenomegaly and hostile marrow microenvironment, which raise concerns for delayed engraftment and graft failure. Methods We performed a retrospective review of the 58 adult patients who received AlloHSCT for MF in British Columbia, Canada, in the 20-year period between January 2001 and December 2020. Data pertaining to patient demographics, disease characteristics, treatment/transplant details and clinical outcomes were gathered from the available paper and electronic records. Relapse-free survival (RFS) was defined as the time between the day of the transplant and the day of disease relapse or death from any cause. Overall survival (OS) was defined as the time between the day of the transplant and death from any cause. Patients who did not have an event during follow up were censored at the time of the last known follow up. Survival analysis was performed by Kaplan-Meier survival estimator and log-rank test, using Stata version 16.1 (Texas, USA). Results The median age of the cohort was 56 years (range 26-68), with 36% being 60 years old or older. The male to female ratio was 1.6:1. The median Karnofsky Performance Status index was 80 (range 70-100) and the median age-adjusted HCT-specific Comorbidity Index was 2 (range 0-5). The pre-transplant DIPPS plus risk category was: high in 13 patients (22%); intermediate-2 in 29 (50%); intermediate-1 in 15 (26%); and low in 1 (2%). 19/58 (33%) had a peripheral blast percentage greater than 2%. 51/58 (88%) had grade 3 fibrosis seen on the pre-AlloHSCT bone marrow biopsy. 27/57 (47%) patients were transfusion-dependent for pRBC and/or platelets. 28/54 (52%) evaluable patients had a normal karyotype and 6/54 (11%) a complex karyotype. Sixteen patients (28%) had a myeloid gene panel performed by PCR; the most commonly seen variants were ASXL1 (10 patients) and TET2 (5 patients). The median number of variants seen in a single patient was 3 (range 0-5). 42/58 (72%) patients received myeloablative conditioning before AlloHSCT. The donor type was: a volunteer unrelated donor in 54%; a matched sibling in 42%; and an alternative source (double cord or haploidentical donor) in 4%. Peripheral blood stem cells were used in 93% of the AlloHSCT. 24/58 (41%) patients received ruxolitinib pre-AlloHSCT (starting in June 2012) for a median duration of 10 months (range 1-44); 17/24 (71%) of the recipients had a clinical response to ruxolitinib but 3 had lost the response before their AlloHSCT. One patient had stopped ruxolitinib due to cytopenia. During a median follow up period of 41.7 months (range 0.5-260.7), 24/58 (41%) experienced acute graft-versus-host disease (GVHD) and 33/49 (67%) evaluable patients developed chronic GVHD. Graft failure was seen in 2 patients - one primary and the other secondary. MF relapse was seen in 13/58 (22%) after a median time of 1.1 years post-AlloHSCT (IQR 0.7-2.4). The transplant-related mortality (TRM) was 25% at 1 year and 28% at 3 years post-AlloHSCT. The most common causes of death were infection (7 patients), disease relapse (6 patients), and multiorgan failure (5 patients). Transfusion independence was achieved in 45/58 (78%) patients by day +100 and in 40/44 (90%) by 1-year post-AlloHSCT. 17/48 (35%) evaluable patients had persistent grade 3 fibrosis on their day+100 bone marrow biopsy. The estimated 1-year, 5-year and 10-year RFS rates were 66% (95% CI 52-76), 55% (95% CI 41-67) and 47% (95% CI 42-61) respectively. The estimated 1-year, 5-year and 10-year OS rates were 72% (95% CI 59-82), 63% (95% CI 49-74) and 54% (95% CI 37-68) respectively. There were no differences in RFS (p=0.40) and OS (p=0.23) between those who received ruxolitinib pre-transplant vs. those who did not. Conclusion In our cohort, approximately half the AlloHSCT recipients achieved long-term survival, many in remission (10-year OS 54%; 10-year RFS 47%). TRM was seen in 25% within the first year after AlloHSCT, with patients most commonly succumbing to infections. The graft failure rate was low at 3%. An increasing number of patients received pre-AlloHSCT ruxolitinib in the recent years but we were unable to demonstrate improved transplant outcomes with its use in this single centre cohort.

Treosulfan Compared to Busulfan in Allogeneic Haematopoietic Stem Cell Transplantation for Myelofibrosis: A Registry-Based Study from the Chronic Malignancies Working Party of the EBMT

Background The optimal conditioning prior to allogeneic stem cell transplantation (HSCT) for myelofibrosis (MF) remains an ongoing matter of debate. There is a paucity of randomized trials robustly showing superiority of one over another. Registry studies comparing reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC) regimens did not show significant differences in overall survival (OS). Recently, a multi-center phase 3 trial in MDS-AML reported an advantage of fludarabine-treosulfan (TREO) over fludarabine-busuflan (BU) RIC (Lancet Haematol Beelen et al 2020). The role of this large EBMT registry study was to compare outcomes of MF HSCT following TREO and BU based MAC or RIC regimens. Methods Patients with MF transplanted from a T-cell replete graft between 2010-2018 following BUMAC, BURIC or TREO were identified in the EBMT registry. Patients who were transformed into AML were excluded. Centers were contacted to participate in additional data collection. 63 centers included a total of 536 patients of whom 6 patients were excluded due to missing data for major endpoints (relapse or regimen). The role of TREO was tested in multi-variable models adjusted on major prognostic factors especially those who were not well balanced between groups and using multiple imputation for missing values. Results Most TREO (n=73) patients received it in combination with FLUDARABINE (95%) and most BU (n=457) received FLUDARABINE +/- other (93%). Median total dose received of TREO was 42 g/m2 and median dose of BU was 8mg/kg. Main differences between the 3 groups were: 1) Recipient age; patients were the oldest in the RIC group (median age 61 years, (IQR: 55-65), the youngest in BUMAC (56 years, (IQR: 51-62)), and intermediate in the TREO group (59 years, (IQR: 54-64); 2) Performance status; Karnofsky score was < 80 in 20%, 30%, 42% in the TREO, BUMAC and BURIC groups, respectively; 3) Comorbidity score (HCT-CI) was lowest in the MAC group (HCT-CT ‘low’ in 56%, 45% and 37% of BUMAC, BURIC and TREO groups); 4) Disease status; patients in the TREO group were more often transplanted with progressive disease (58% vs 30% in BUMAC and 34% in BURIC); 5) JAK inhibitor prior to HSCT; a higher proportion of patients in the TREO group were treated with a JAK inhibitor before HSCT (61% vs 50% in BUMAC and 42% in BURIC); 6) Cytomegalovirus (CMV) donor/ recipient status; CMV combinations were more frequently donor recipient -/- in the TREO cohort (41% vs 28% in MAC and 36% in RIC); 7) an HLA matched sibling donor was less frequently used in TREO group (18% vs. 28% in BURIC and 36% in BUMAC). The 3 groups were well balanced regarding period of transplantation, MF classification (primary versus secondary), splenomegaly at time of transplantation, chromosome abnormalities, MF related symptoms, DIPSS score, GVHD prophylaxis and use of ATG. Median time to neutrophil recovery was 17 days (range: 6-54), with no differences between the 3 groups. Cumulative incidence of engraftment at day 30 was 91.5% (95%CI: 89.1-93.9), with no differences between the 3 groups. Cumulative incidence of grade 2-4 acute GVHD at 120 days for the entire cohort was 23% (95%CI: 19-26%); similar in the 3 groups. Three-year OS was 62% (95% CI 58 -66), 3-year PFS was 49% (45-53). At 3 years, cumulative incidence of relapse was 26% (22-29) and NRM was 25% (21-29). Figure 1 shows OS, PFS, NRM and cumulative incidence of relapse (CIR) according to regimen. Multiple variables Cox models after selection are shown in Table 1. TREO group had a significantly better OS than BUMAC (HR: 0.61, 95%CI: 0.39-0.93), BURIC had similar OS to BUMAC (HR: 0.92, 95%CI: 0.68-1.26) and there was a trend for a better OS with TREO over BURIC (HR: 0.66, 95%CI: 0.41-1.05). The same trend was also observed for PFS with a significant advantage of TREO over BUMAC (HR: 0.57, 95%CI: 0.38-0.84) and BURIC (HR: 0.60, 95%CI: 0.39-0.91) while BURIC had a similar risk to BUMAC (HR: 1.05, 95%CI: 0.80-1.39). The improvement of OS and PFS was related to a lower NRM (HR: 0.44, 95%CI: 0.24-0.80 TREO vs BUMAC; HR: 0.54, 95%CI: 0.28-1.04 TREO vs BURIC) and same relapse risk with TREO over BU (TREO vs BUMAC, HR: 0.71, 95%CI: 0.42-1.20; TREO vs BURIC, HR: 0.63, 95%CI: 0.36-1.11). Conclusion TREO based regimens compared to BU based shows better PFS in MF HSCT. This advantage was also confirmed for OS and NRM when compared to BUMAC. More specific prospective studies are needed to confirm findings from this registry based study.

Allogeneic haematopoietic stem cell transplantation for myelofibrosis: prognostic indicators and the role of JAK2V617F measurable-residual disease monitoring by droplet-digital polymerase chain reaction.

Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is one of the key determinants of outcome in myelofibrosis (MF) and remains an important unmet need. In this retrospective single-centre study, we evaluated 35 consecutive patients with MF receiving allogeneic HSCT. At 30 days post-HSCT, full donor chimerism was achieved in 31 patients (88.6%). The median time to neutrophil engraftment was 16.8 (10-42) days and the median time to platelet engraftment was 26 (12-245) days. Four patients (11.4%) experienced primary graft failure. With a median duration of follow-up of 33 (1-223) months, with the 5-year overall survival (OS) and progression-free survival (PFS) were 51.6% and 46.3%, respectively. Relapse after HSCT (P < 0.001), leucocyte count ≥ 18 × 109/L at HSCT (P = 0.003) and accelerated/blast phase disease at HSCT (P < 0.001) were significantly associated with worse OS. Age at HSCT ≥ 54 years (P = 0.01), mutated ETV6 (P = 0.03), leucocyte count ≥ 18 × 109/L (P = 0.02), accelerated/blast phase MF (P = 0.001), and grade 2-3 bone marrow reticulin fibrosis at 12 months post-HSCT (P = 0.002) were significantly associated with worse PFS. JAK2V617F MRD ≥ 0.047 [sensitivity 85.7%; positive predictive value (PPV) 100%; AUC 0.984; P = 0.001] at 6 months and JAK2V617F MRD ≥ 0.009 (sensitivity 100%; PPV 100%; AUC 1.0; P = 0.001) at 12 months were highly predictive of post-HSCT relapse. Inferior OS and PFS were significantly associated with detectable JAK2V617F MRD at 12 months (P = 0.003 and P = 0.0001, respectively).

Spleen volume and length determined by computed tomography impact outcome after allogeneic stem cell transplantation for myelofibrosis.

Splenomegaly is a hallmark of myelofibrosis (MF), and reports on the impact of spleen size on the outcome of allo-HSCT have been conflicting, possibly due to differences in methods of assessment. We retrospectively analysed the impact of spleen volume and length measured by computed tomography on allo-HSCT outcome in 93 patients, 74% of whom had prior ruxolitinib treatment. Median spleen volume and length were 1.58 dm3 and 20 cm, respectively. We found a strong correlation between spleen volume and length (Pearson's r = 0.95, p < 0.001), Spearman (rho = 0.96, p < 0.001). After a median follow-up of 41.7 months, 5-year overall and disease-free survival were 66% and 59%, respectively. Spleen size did not impact overall survival or non-relapse mortality. Larger spleen volume and length as continuous variables were associated with slower platelet and leucocyte engraftment and a higher risk of disease relapse in univariate and multivariate analyses. Spleen length measured precisely by imaging is a good surrogate for spleen volume. In the era of JAK inhibitors, larger spleen size reflects advanced disease in MF and is associated with an increased risk of relapse but has no impact on non-relapse mortality and overall survival after allo-HSCT.

Allogeneic stem cell transplant for myelofibrosis- A retrospective single-center study.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment option for myelofibrosis (MF). Despite the benefits of long-term relapse-free survival, HSCT can be associated with substantial treatment-related morbidity and mortality. This is an observational retrospective study of 15 consecutive patients with MF who underwent allogeneic HSCT at a tertiary care center in Northern India between June 2012 and January 2020. The pre-transplant Dynamic International Prognostic Scoring System (DIPSS) and hematopoietic cell transplantation-specific co-morbidity index (HCT-CI) scores were used. The primary endpoints were overall survival (OS) and disease-free survival (DFS), and the secondary endpoints were post-transplant complications (acute and chronic graft-versus-host-disease [GvHD], graft failure [GF], and cytomegalovirus reactivation [CMV]). The OS and DFS in our study were 60% with no relapse at a median follow-up of 364 days (range 7-2,815 days). Twenty-seven percent of patients developed acute GvHD and 27% of patients developed chronic (limited) GvHD. The non-relapse mortality (NRM) was 40%, with the main cause of death being sepsis, followed by acute GvHD. MF remains a challenging condition to treat, with a poor prognosis. Our study showed that reduced toxicity conditioning provided good DFS and OS. Thus, it should be offered to patients with high DIPSS scores. Sepsis was the predominant cause of mortality in this cohort.

Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: Role of Disease Status and Chimerism on Long-Term Outcomes

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative option for Myelofibrosis (MF), a myeloproliferative neoplasm characterized by severely reduced survival. Despite a recognized superiority of transplant compared to medical options in higher risk MF, short-term complications substantially limit its use. Also, relapse can occur in a significant proportion of patients after allo-HCT. In this regard, controversial results have been reported on the predictive role of mixed chimerism. While CD33+ mixed chimerism was reported to correlate with worse OS due to higher risk of both relapse and non-relapse mortality (NRM), incomplete CD3+ chimerism was associated to an improved relapse-free survival. However, CD33 and CD3 antigens may not represent optimal markers for MF, since their expression, in contrast to CD34 antigen, has never been extensively described in MF. Herein we present a single Center experience on MF allo-HCT patients periodically monitored with CD34+, CD34- and mononuclear cells (MNC) donor chimerism with the aim to evaluate predictive factors for transplant outcome. Patients and methods. Overall, 31 MF patients were transplanted at the Unit of Bone Marrow Transplant of ASST Spedali Civili of Brescia from May 2014 to June 2022. Patients’ characteristics at time of transplant are detailed in table 1. Regarding transplant features, 15 patients received a myeloablative conditioning and 20 double-alkylators regimen (TBF in 19 and BuCy in 1 case). Donor was sibling, unrelated or haploidentical in 22.6%, 51.6% and 25.8% of cases. HCT-CI was high in 45.2%, FIL score unfit in 9.7% and KPS was 80 or less in 6.5% of cases, respectively. After transplant, the large majority of surviving patients underwent 1, 3, 6, 9, 12, 18 and 24-month donor chimerism, by using single tandem repeats (STR) PCR on patients’ bone marrow samples. Kaplan Meier was employed for computing OS. The Fine and Gray method was used for NRM and incidence of relapse (CIR). Three- and 6-month landmark analysis was utilized in order to evaluate the effect of mixed chimerism on outcomes. Univariate and multivariate analyses for OS were carried out using the Cox regression model. Logistic regression was employed for identifying factors associated with full donor chimerism. Results. After a median follow-up of 2.33 years (95%CI 1.02-3.20), 15 patients had died (6 relapse, 3 acute GVHD, 3 infections, 3 other causes) for a 5y CIR, NRM and OS of 21.7% and 30.5% and 48.6%. In Univariate analysis, high risk DIPSS (HR 3.91, 95%CI 1.40-10.95, p=0.009), FIL unfitness (HR 7.00, 95%CI 1.71-28.73, p=0.007), unfavorable cytogenetics (HR 4.88, 95%CI 4.88-1.36-17.49, p=0.015), accelerated phase disease (HR 3.84, 95%CI 1.32-11.17, p=0.013) and spleen palpable >15 cm below LCM (HR 4.50, 95%CI 1.49-13.53, p=0.008) were associated to reduced survival. In Multivariable analysis, accelerated phase disease (HR 8.03, 95%CI 1.68-38.52, p=0.009), splenomegaly (HR 15.64, 95%CI 3.12-78.47, p<0.001) and FIL unfitness (HR 33.43, 95%CI 3.97-281.40, p=0.001) maintained prognostic information. Importantly, high risk mutations did not prove any ability to predict survival after transplant (HR 1.60, 95%CI 0.51-4.98, p=0.420). Figure 1 illustrates the evolution of chimerism over time. Interestingly, 3 and 6-month MNC, CD34+ and CD34- mixed donor chimerism (<97.5%) was associated with significantly reduced survival (3-month landmark OS: 92.9% vs 20.0% [p=0.001], 100% vs 33.3% [p=0.003] and 100% vs 0% [p<0.001] at 1y; and 6-month landmark OS: 100% vs 0% [p<0.001], NA [only one patient with <97.5% donor chimerism], and 100% vs 0% [p=0.002] at 1 year, respectively), caused by increased CIR (data not shown). Double alkylator (HR 14.70, 95%CI 1.16-185.00, p=0.038) was the only parameter predicting an higher probability of reaching full donor chimerism after allo-HCT. Conclusions. Our study confirms the efficacy and safety of early transplant in MF. Patients submitted for transplant with massive splenomegaly or advanced stage disease appear to have a poor outcome. In addition, multidimensional geriatric assessment may represent an effective method to select MF allo-HCT candidates. The early achievement of full donor chimerism, as evaluated on MNC and CD34 lineages can predict a reduced risk for relapse and long-term survival. In this regard, use of double alkylating conditioning regimen could be relevant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Training and Validation Cohorts for Predicting the Impact of High Molecular Risk Mutations after Allogeneic Stem Cell Transplantation in Myelofibrosis

Introduction Myelofibrosis (MF) is the most aggressive form of Philadelphia negative myeloproliferative neoplasm and allogeneic hematopoietic stem cell transplantation (HSTC) is the only curative approach, but non relapse mortality limits the indication for HSTC to high-risk patients. The prognostic evaluation of MF patients is evolving during time together with a better understanding of the mutational landscape of this disease. The presence of high molecular risk (HMR) mutations, specifically ASXL1, SRSF2, EZH2, IDH1, IDH2 and U2AF1Q157, harbors a detrimental effect on survival and leukemic transformation and has been incorporated in different prognostic scoring systems. In this multicenter study we aimed to determine the impact of HMR mutations on transplant outcome. Methods We studied two independent cohorts of patients: 44 patients (training, retrospective cohort) were part of a multicenter, randomized GITMO (Gruppo Italiano Trapianti di Midollo Osseo) clinical trial (Patriarca F, BBMT 2019) and 29 patients (validation, prospective cohort) were subsequently recruited at the Bergamo Bone Marrow Transplant Unit. Patients from the training cohort (median age 56, range 36-66) were conditioned with busulfan-fludarabine or thiotepa-fludarabin while patients in the validation cohort (median age 61, range 36-67) were conditioned with a reduced intensity thiotepa-busulfan-fludarabin regimen. The mutational profile obtained on the pre-transplant DNA was performed by sequencing 30 myeloid related genes by applying SOPHia GENETICS Myeloid Solution on Illumina MiniSeq platform. Results In the training retrospective cohort, driver mutations were detected in 40 (29 JAK2/8 CALR/3 MPL) patients, with 4 patients having a triple negative MF. At least one HMR mutation was detected in 43% of patients and an unfavorable karyotype was present in 18% of patients. According to the Mutation-Enhanced International Prognostic Scoring System 70 plus (MIPPS70+) scoring system, 77% of patients were allocated in the high/very high groups. With a median follow up of 4.2 years (range 0.02-9), the 5-years Overall Survival (OS) and Progression Free Survival (PFS) were 61% and 45% respectively. The 5-years Non-Relapse Mortality (NRM) and Cumulative Incidence of Relapse (CIR) were 25% and 30%. In the prospective validation cohort, a driver mutation was detected in all patients (15 JAK2/7 CALR/7MPL). At least one HMR mutation was detected in 48% of patients and an unfavorable karyotype was present in 24% of patients. Patients allocated to the MIPPS70+ high/very group were 52%. After a median follow up of 10.7 months (range 0-44), the 2-years OS and PFS were 61% and 49% respectively. The 2-years NRM and CIR were 33% and 18%. In the training cohort, a higher risk of death and progression was observed in patients with high/very high risk MIPPS70+ prognostic index [HR for OS 4.3 (95% CI 0.6-33.1), HR for PFS 4.1 (95% CI 0.9-16.9)]. Conversely, the presence of HMR mutations did not significantly affect OS, PFS (Figure 1), NRM or CIR. The prognostic significance of MIPSS70+ risk classification was confirmed in the validation cohort, with a higher risk of death and progression for high/very high MIPSS70+ group [OS HR 3.2 (95% CI 0.4-27.1), PFS HR 3.8 (95% CI 0.5-31.4)]. Similarly, in the validation cohort the presence of HMR mutations did not affect transplant outcome, with no impact on OS, PFS (Figure 2), NRM or CIR. In the whole group of 73 patients, the presence of JAK2V617F mutation showed an adverse prognostic impact on CIR [HR 3.4 (95% CI 1-11.8)], while MIPPS70+ confirmed its role on PFS. Conclusions In this study we prospectively confirmed that the presence of HMR mutations did not impact on transplant outcome. Allogeneic stem cell transplantation can lead to a significant cure rate of MF patients, regardless the presence of HMR mutations. Patients in the high/very high MIPSS70+ risk group had a higher risk of death and progression after transplant. Appropriate timing and selection of patients is crucial for transplant outcome in MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

2021 Update on allogeneic hematopoietic stem cell transplant for myelofibrosis: A review of current data and applications on risk stratification and management

The number of patients with myelofibrosis (MF) undergoing an allogeneic hemopoietic stem cell transplantation (HSCT) is increasing: in the analysis of the European Group for Blood and Marrow Transplantation (EBMT) the number of MF has increased from 515 in 2014 to 748 in 2018 . This reflects the fact that HSCT is currently the only curative treatment, capable of inducing prolonged disease‐free survival. Nevertheless, several problems prevent more patients from undergoing an allogeneic HSCT: we will be discussing indications for HSCT, comorbidities, splenomegaly, older age and disease phase. Donor type and stem cell source are less of a problem. Several transplant platforms exist, including different strategies for graft versus host disease (GvHD) prophylaxis, Age tailored conditioning regimens need to be implemented, to allow older and fragile patients to undergo an allogeneic HSCT.

Transfusion Dependence at Day +100 Predicts Poorer Outcomes in Patients Undergoing Allogeneic Stem Cell Transplantation for Myelofibrosis

Introduction - Various pre-transplantation factors help predict outcomes in patients (pts) with myelofibrosis (MF) undergoing allogeneic stem cell transplantation (HCT). However, early post-HCT characteristics have not been correlated with outcomes. Our study aims at identifying day +100 characteristics that are indicative of poorer outcomes.Methods - Pts undergoing HCT for MF at the 3 sites of Mayo Clinic in Rochester, Arizona and Florida, between January 2005 and August 2016, were retrospectively reviewed for collecting baseline, disease, transplantation and outcome data. Day +100 data was collected as available between day +80 through day +120. Day +100 characteristics included molecular status, WHO grade of bone marrow fibrosis, spleen size, red blood cell (RBC) transfusion dependence and platelet transfusion dependence. Transfusion dependence was defined as RBC or platelet transfusions requirements of 2 units in a 4 week period. Since there was limited data on donor chimerism and molecular marker status over the years, we used a variable called “molecular status” to reflect on the molecular response after HCT. Molecular status was defined as favorable if either 100% donor chimerism in CD33 fraction from blood or molecular marker negativity was known and as unfavorable if donor chimerism <100% or molecular marker positivity was known at day +100. Survival analysis was conducted using Kaplan-Meier (K-M) survival curve and a series of univariate and multivariate Cox proportional hazard regression models. Patient characteristics measured at day +100 along with age at HCT, gender, Dynamic International Prognostic Scoring System (DIPSS)-Plus score, conditioning regimen (myeloablative vs reduced intensity) and donor source (related vs unrelated) were used to examine group differences in K-M curves and to predict overall survival in the regression models.Results -Baseline/ Transplantation characteristics : A total of 87 pts underwent HCT for MF, of which, 79 were included in our study. Eight pts who died within 80 days from HCT were not included in the analysis. Median age at HCT was 58 years (range, 19-73 years). Forty seven (60%) were men and MF was primary in 54 (68%) pts. DIPSS-Plus score was high in 34 (43%), intermediate-2 in 40 (51%) and intermediate-1 in 5 (6%) pts. Conditioning regimen was myeloablative in 14 (18%) and reduced intensity in 65 (82%). Anti-thymocyte globulin was used in 35 (44%) pts. Donor source was related in 39 (49%) and unrelated in 40 (51%) pts. Of the related donors, 2 were haploidentical donor HCTs. JAK2 mutation was positive in 41 (54%) out of 76, CALR was positive in 8 (38%) out of 21 and MPL was positive in 4 (13%) out of 31 pts, in whom the status was available. Forty three (57%) pts were ABO compatible while 19 (25%) had minor ABO incompatibility, 12 (16%) had minor incompatibility and 1 (1%) had bidirectional ABO incompatibility. Ten (13%) pts had undergone splenectomy prior to HCT.Survival analysis : Twenty-six (33%) pts had died at the time of this study. Cause of death was HCT-related in 19 (73%) and disease relapse/ progression in 7 (27%) pts. RBC transfusion dependence, platelet transfusion dependence and unfavorable molecular status at day +100 were associated with increased risk of death in the univariate model (Table 1). The significant and nearly significant day +100 predictors from the univariate models were included in the multivariate model (table 2) along with pre-transplant characteristics. RBC and platelet transfusion dependence were significant predictors associated with poorer overall survival in the multivariate analysis (hazard ratios 30.18 and 8.43, respectively). Bone marrow fibrosis of grade ≥ 2 showed a trend towards poorer OS in the univariate analysis, but was not statistically significant in the multivariate model (hazard ratio 5.44, p= 0.08).Conclusions - In this exploratory analysis of day +100 variables for predicting long-term outcomes in pts undergoing HCT for MF, we report a strong relationship between RBC/ platelet transfusion dependence at day +100 and increased risk of death (figure 1). The mechanism of this relationship is not clear. These pts could, perhaps, benefit from close monitoring or early intervention. Given the scope of the current study, larger studies are warranted to further investigate these findings and identify the cause of this association. [Display omitted] DisclosuresKhera:Novartis: Consultancy. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; Gilead Sciences, Inc.: Research Funding; Incyte Corporation: Research Funding; Ariad: Consultancy; Promedico: Research Funding; Celgene Corporation: Research Funding; CTI BioPharma Corp.: Research Funding; Galena Biopharma, Inc.: Consultancy.

Pre-Transplantation Predictors of Survival in Patients Undergoing Allogeneic Stem Cell Transplant for Myelofibrosis

Background:Allogeneic stem cell transplantation (HCT) is a potentially curative therapy for patients with myelofibrosis (MF). Factors associated with survival in the literature include donor source, age, conditioning regimen, and spleen size prior to transplant. We reviewed the transplant outcomes from Mayo Clinic from the last 10 years to identify pre-transplant factors associated with survival.Methods:Patients undergoing HCT for MF at the 3 sites of Mayo Clinic in Rochester, Arizona and Florida, between January 2005 and August 2016, were retrospectively reviewed. Survival analysis was conducted using Kaplan-Meier (K-M) analysis and a series of univariable and multivariable Cox proportional hazard regression models. Patient characteristics measured before bone marrow transplant procedure along with patient's age, gender, transfusion dependence, and Dynamic International Prognostic Scoring System (DIPSS)-Plus score, and transplant characteristics including conditioning regimen (Reduced intensity conditioning (RIC) vs myeloablative conditioning (MAC)), donor (related vs unrelated), and graft versus host disease (GVHD) prophylaxis (Calcineurin inhibitor (CNI) +methotrexate (MTX) or CNI + mycophenolate mofetil (MMF)), and number of anti-thymocyte globulin (ATG)doses administered (dose 2.5 mg/kg; grouped as 0 doses, 1 dose, or 2-3 doses) were used to examine differences in K-M curves and to predict overall survival in the regression models.Results:There were 87 patients included in this analysis. The median age at HCT was 58 (19-73), and there was a male predominance (n=52, 60%). Sixty patients (69%) had primary MF, and the remainder had secondary MF. The DIPSS plus score was high risk in 37 (43%), Intermediate-2 risk in 45 (52%), and Intermediate-1 risk in 5 (6%) patients. JAK2 mutation was present in 41(47%). A RIC regimen was used in 73 (84%). ATG was given in 37 patients (43%). The median time to platelet and neutrophil engraftment were 23 days (8-116) and 17 (10-166) respectively. There were 13 patients who never engrafted platelets, and 3 patients who never engrafted neutrophils. At the time of last follow up, 53 (61%) patients were alive. Relapse occurred in 12 (14%) patients. With a median of 37.2 (5-629) months follow up, the overall probability of survival was 66% (95% CI 57-77%) at 2 years, and 57% (95% CI 46-70%) at 5 years. Treatment related mortality occurred in 25 patients (29%), relapse related mortality was found in 8 (9%). Grade 2-4 acute GVHD occurred in 49 (56%) and grade 3-4 GVHD occurred in 28 (32%). Chronic GVHD occurred in 33 (45%), 7 (21%) were mild, 19 (58%) were moderate, and 7 (21%) were severe.Of the characteristics considered, ATG dose, donor source, and RBC transfusion dependency showed a significant difference in survival between groups (p < .05) (See Figure). In the multivariable analysis, (See table) one dose of ATG as compared to no doses was significantly associated with increased survival [HR = 0.31 (0.12-0.82), p < .05]; unrelated donor source [HR = 2.2 (1.01-4.78), p= .05] and RBC transfusion dependence [HR=2.36 (0.96-5.83), p= 0.06] were associated with an increased risk of death but these relationships were not statistically significant. This model was adjusted for age, but age was not significantly related to increased risk of death [HR = 1.23 (0.57-2.69), p= .60].Discussion:In our retrospective analysis of patients undergoing HCT for MF, there were several notable findings. Receipt of low dose ATG was associated with a favorable survival, whereas, need for RBC transfusion pre-HCT and unrelated donor were associated with a trend towards increased risk of death. This association of low dose ATG use and improved survival as seen in our study would need to be studied in larger prospective study to further elucidate the reasons and validate of these findings. [Display omitted] DisclosuresKhera:Novartis: Consultancy. Mesa:Incyte Corporation: Research Funding; CTI BioPharma Corp.: Research Funding; Gilead Sciences, Inc.: Research Funding; Galena Biopharma, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Celgene Corporation: Research Funding; Ariad: Consultancy; Promedico: Research Funding.

Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT

JAK1/2 inhibitor ruxolitinib (RUX) is approved in patients with myelofibrosis but the impact of pretreatment with RUX on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) remains to be determined. We evaluated the impact of RUX on outcome in 551 myelofibrosis patients who received HSCT without (n = 274) or with (n = 277) RUX pretreatment. The overall leukocyte engraftment on day 45 was 92% and significantly higher in RUX responsive patients than those who had no or lost response to RUX (94% vs. 85%, p = 0.05). The 1-year non-relapse mortality was 22% without significant difference between the arms. In a multivariate analysis (MVA) RUX pretreated patients with ongoing spleen response at transplant had a significantly lower risk of relapse (8.1% vs. 19.1%; p = 0.04)] and better 2-year event-free survival (68.9% vs. 53.7%; p = 0.02) in comparison to patients without RUX pretreatment. For overall survival the only significant factors were age > 58 years (p = 0.03) and HLA mismatch donor (p = 0.001). RUX prior to HSCT did not negatively impact outcome after transplantation and patients with ongoing spleen response at time of transplantation had best outcome.

The value of bone marrow, liver, and spleen imaging in diagnosis, prognostication, and follow-up monitoring of myeloproliferative neoplasms: a systematic review

BackgroundDiagnostic and treatment response criteria for the JAK2/CALR/MPL mutation-related myeloproliferative neoplasms (MPNs) are largely based on bone marrow (BM) biopsy results. However, these biopsies have several limitations, such as the risk of sampling error. Also, the prognostic impact of BM abnormalities is largely unclear. Although not currently used in clinical practice, imaging techniques might offer additional information. In this review, we investigated the value of BM, liver, and spleen imaging for diagnosis, prognostication, and response monitoring of the JAK2/CALR/MPL mutation-related MPNs (i.e. essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)).MethodsA systematic literature search was performed via PubMed, Embase and the Cochrane Library up to 2020 March 26th. Of 5505 identified records, 55 publications met the eligibility criteria (i.e. containing original data on the imaging appearance of BM, spleen, or liver in adult ET, PV, or MF patients, published in a peer-reviewed journal, written in English).ResultsMany explorative studies described imaging features, sometimes with comparisons to clinical characteristics. Studies reporting measures of diagnostic accuracy included 1) splenic transient elastography to predict BM fibrosis grade in MF, 2) dynamic contrast-enhanced MRI to discern MF patients from ET patients and healthy controls, and 3) 18-fluorodeoxyglucose PET to detect residual disease after stem cell transplantation in MF. The diagnostic accuracies of radiography and 99mTc-colloid scintigraphy were derived from several other articles. Except for the study on 18-fluorodeoxyglucose PET, we established substantial concerns regarding risk of bias and applicability across these studies, using the QUADAS-2 tool. Three publications described a correlation between imaging results and prognosis, of which one quantified the effect.ConclusionsBased on current data, MRI (T1-weighted/STIR, Dixon) seems especially promising for the evaluation of BM fat content - and indirectly cellularity/fibrosis - in MF, and possibly for estimating BM cellularity in ET/PV. 18-fluorodeoxyglucose and 18-fluorothymidine PET/CT might be useful for evaluating BM fibrosis, with good reported accuracy of the former for the diagnosis of residual disease. Further research on these and other techniques is warranted to determine their exact value. Future researchers should improve methodology and focus on evaluation of diagnostic accuracy and prognostic implications of results.

154 - Impact of Conditioning Regimen and Donor Type on Outcomes of Allogeneic Stem Cell Transplant for Myelofibrosis – a Single Institutional Experience

154 - Impact of Conditioning Regimen and Donor Type on Outcomes of Allogeneic Stem Cell Transplant for Myelofibrosis – a Single Institutional Experience

170 - Allogeneic Hematopoietic Stem Cell Transplant for Myelofibrosis in Brazil: Facing Our Challenges

170 - Allogeneic Hematopoietic Stem Cell Transplant for Myelofibrosis in Brazil: Facing Our Challenges

Trends in Allogeneic Stem Cell Transplantation for Myelofibrosis in Europe between 1995-2018: An EBMT Retrospective Analysis

Aim: Dynamic assessment of trends over time in patient- and transplant-specific characteristics and outcomes for patients undergoing 1st allogeneic haematopoietic cell transplant (allo-HCT) for Myelofibrosis (MF). Methods and Results: A total of 4142 MF patients were analysed who underwent allo-HCT between 1995-2018 (24-year period) across 278 centres based on data reported to the European Society for Blood and Marrow Transplantation. For analysis, 4 cohorts were considered based on year of allo-HCT: &amp;lt;2006 n=389 (9.4%), 2006-2010 n=910 (22%), 2011-2014 n=1148 (27.7%) and 2015-2018 n=1695 (40.9%). A steady increase in MF allo-HCT activity over time was apparent paralleled with increasing numbers of participating transplant centres. A total of 2603 (62.8%) patients were male, 3239 (78.2%) had Primary MF, 409 (9.9%) and 494 (11.9%) post-Polycythaemia Vera and post-Essential Thrombocythaemia MF, respectively. An increased median interval (lnterquartile range (IQR)) between diagnosis and transplant was evident over time (&amp;lt;2006 median 20.8 (8.9-62.2) months versus 36.2 (11.6-107.5) months in 2015-2018 period;p&amp;lt;0.001), potentially reflecting increased availability of therapeutics in recent eras (untreated patients &amp;lt;2006= 59.4% versus 2015-2018=23.7%). Median recipient age (IQR) increased over time by ~ a decade between earliest cohort and most recent: &amp;lt;2006, 49.4 years (43.1-55.3) versus 59.3 years (53.4-64.8)2015-2018. Prior to 2006, patients &amp;gt;60 years accounted for 8.7% of adults undergoing allo-HCT whereas for 2015-2018 this was 47%. Over time, increasing number of patients with a Karnofsky performance status (KPS) &amp;lt;90 underwent allo-HCT (&amp;lt;2006=19.7% versus 36.1% 2015-18; p&amp;lt;0.001). Peripheral Blood (PB) was the predominant stem cell source and utilisation increased over time, accounting for 74.8% &amp;lt;2006 and 92.2% within 2015-2018 cohort. Cord blood utilisation was limited to &amp;lt;1% throughout the 24-year study period. Significant shifts towards use of unrelated donors (URD) in more recent periods was apparent (p&amp;lt;0.001). Moreover, increased use of mismatched related donors (MMRD) was particularly evident in 2015-2018 cohort; n=152 (9%) versus n=74 (3%) cumulative for other 3 cohorts combined; p&amp;lt;0.001. Decreased use of myeloablative and TBI- based conditioning was evident over time (p&amp;lt;0.001). Specifically, there was increased use of busulphan-based regimens (&amp;lt;2006: 44.2% versus 2015-2018: 72%). Regarding T cell depletion, trends demonstrated increased use of anti-thymocyte globulin (ATG) over time (&amp;lt;2006=37.3% vs 69.9% 2015-2018; p&amp;lt;0.001). Median time to both neutrophil (median 18 days across all cohorts) and platelet engraftment was similar in all 4 cohorts, with no significant variation when stratified by period of transplantation. Allo-HCT outcomes, survival, GVHD and relapse endpoints are shown for all 4 cohorts in Table 1. Overall for the entire group, significant factors associated with worse OS, RFS and NRM remained older age and a poor KPS (&amp;lt;90). No significant differences between cohorts were noted for either estimated 3-year OS (&amp;lt;2006=55% (50-60%), 2006-2010=60% (56-63%), 2011-2014 and 2015-2018= 58% (55-61%); p=0.299) or non-relapse mortality (NRM (Table 1); p=0.523), despite increasing numbers of older, less fit patients, and more frequent HLA-mismatched transplants over time. To investigate survival findings in more detail an adjusted model will be presented including period of allo-HCT and transplant-related variables. Cumulative incidence of relapse at 3 years was similar across all cohorts, suggesting no significant changes with time. Most common causes of death across all 4 cohorts remained GVHD and infection. Of note, rates of acute (a)GVHD grade II-IV by day +100 decreased from the earliest cohort &amp;lt;2006 compared to the later groups (p=0.027) as did rates of overall chronic (c) GVHD whereby this was evident in 57% (95% CI 52-62%) &amp;lt;2006 cohort compared to 44% (95% CI 42-47%) in the 2015-2018 group, predominantly reflected by reductions in extensive cGVHD (Table 1). Conclusions: Despite a marked increase over this 24-year period in recipient age, RIC regimen utilisation and use of both URD and MMRD, this comprehensive analysis demonstrates stable OS and EFS rates. However, rates of GVHD have decreased over time, in particular extensive cGVHD. Further work is required to improve both the considerable NRM and relapse rates which remain significant. Disclosures McLornan: JAZZ PHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau; NOVARTIS: Honoraria, Speakers Bureau. Platzbecker:Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Chevallier:Incyte Corporation: Honoraria. Martínez-Lopez:Altum, Hosea: Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties; Vivia Biotech: Honoraria; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding. Yakoub-Agha:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria.

Incidence and Outcome of Late Relapse after Allogeneic Stem Cell Transplantation for Myelofibrosis

In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n=6) or hematologic (n=7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n=7) and/or second transplantation (n=4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P=.13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT.

Australasian Trends in Allogeneic Stem Cell Transplantation for Myelofibrosis in the Molecular Era: A Retrospective Analysis from the Australasian Bone Marrow Transplant Recipient Registry.

To review the updated trends of national practice and outcomes in transplantation to treat myelofibrosis (MF), we retrospectively evaluated 142 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) for primary (n=94) or secondary (n=48) MF at an Australian/New Zealand transplantation center between 2006 and 2017. The median duration of follow-up was 51.8 months (range, 3.1 to 148 months). The median age at allo-HSCT was 56 years (range, 26 to 69 years). Fifty-two percent of the patients had HLA-identical sibling donors, and 45% had matched unrelated donors (UD). Conditioning regimens were predominantly reduced intensity (83%). Before transplantation, 16% of the patients had undergone splenectomy or splenic irradiation, and 38% (n=54) received JAK inhibitor therapy. JAK2 mutation testing was performed in 66.9% of the patients, whereas other mutations (CALR, MPL, ASXL1, SRSF2, U2AF1Q57, EZH2, and IDH1/2) were rarely tested (1.4% to 8.4%). Only 4.2% of patients had next-generation sequencing mutation analysis. The median time to neutrophil engraftment was 19 days (range, 10 to 43 days), and the median time to platelet engraftment was 27 days (range, 13 to 230 days). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 21.4% at 100 days, and that of extensive chronic GVHD (cGVHD) at 5 years was 18.1%. Overall survival (OS) was 67% at 1 year and 57% at 5 years. GVHD-free, relapse-free survival was 54% at 1 year and 42% at 5 years. The cumulative incidence of nonrelapse mortality (NRM) was 16% at 100 days and 25% at 1 year. In multivariate analysis, age ≥65 years and use of an UD were identified as significant unfavorable risk factors for OS and NRM. Use of an UD increased the incidence of aGVHD, whereas administration of antithymocyte globulin/alemtuzumab lowered the risk of both aGVHD and cGVHD. Pretransplantation splenectomy/splenic irradiation had a positive influence on time to engraftment. There have been no improvements in the outcomes of allo-HSCT for MF in Australasia over the last decade, with a low uptake of molecular genomic technology due to limited access to funding.

Outcome of Allogenic Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Single-Center Retrospective Analysis

<h3>Objective</h3> To study clinical outcome in patients with Myelofibrosis undergoing Allogenic hematopoietic stem cell transplantation. <h3>Introduction</h3> Allogenic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment option for Myelofibrosis (MF). Despite the benefit of long-term, relapse- free survival with HSCT, it can be associated with substantial treatment-related morbidity and mortality. Therefore careful patient counseling and accurate patient selection is mandatory. <h3>Methods</h3> This is an observational retrospective study including patients with previous diagnosis of MF (primary or secondary) who underwent Allogenic HSCT at a tertiary care centre in Northern India between June 2012 and September 2019. Pre-transplant DIPSS and HCT-CI scores were applied. The primary end points were overall survival and disease free survival (OS and DFS), and secondary end points were post-transplant complications (graft-versus-host-disease [GVHD], graft failure [GF], CMV reactivation [CMV]). (Table 1) <h3>Results</h3> Outcome of SCT given in table 2. <h3>Conclusion</h3> Myelofibrosis remains a very challenging condition to treat with a poor prognosis. Our study shows reduced toxicity conditioning provides a good DFS and OS. Thus it should be offered upfront to patients with high DIPSS scores. Sepsis remains the predominant cause of mortality in our cohort.