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Allogeneic Cell Transplantation for Myeloproliferative Neoplasms
Introduction
Myeloproliferative neoplasms (MPN) are a heterogeneous group of myeloid stem cell disorders shared by certain clinical and biological similarities, and characterized by clonal myeloproliferation without significant dyserythropoiesis, granulocytic dysplasia, or monocytosis. Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) are collectively grouped together under chronic Philadelphia chromosome-negative MPNs compared to the distinguished Philadelphia chromosome-positive chronic myeloid leukemia (CML). In addition to PMF, the World Health Organization defines three additional variants of MF including prefibrotic, post-ET, and post-PV MF. ET and PV have by far the highest incidence rates compared to other MPNs and with an overall excellent long-term prognosis. A subgroup of these patients (up to 15%), however, may progress over time to secondary MF that carries less favorable prognosis. PMF is a less prevalent MPN subtype with approximately 13,000 estimated cases in the United States. The clinical features of these neoplasms can be heterogeneous, ranging from completely asymptomatic disease, presence of constitutional symptoms, symptomatic splenomegaly, symptomatic anemia, thromboembolic and bleeding manifestations, and the inherent risk of leukemic transformation that usually carries poor prognosis. Patients with PMF have generally worse survival compared to PV and ET and to matched healthy controls. CML, on the other hand, accounts for about 15% of adult leukemias and long-term survival has remarkably improved since the introduction of tyrosine kinase inhibitors (TKIs) to approach aged-matched controls.
Despite the advances made in treatments over the past decade, allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for patients with PMF and secondary (post-PV and post-ET) MF. Recent transplant registry studies indicate a notable increase in the use of allo-HCT in MF patients over the past two decades and with notable improvements in survival. In contrary, allo-HCT, which was once a first-line treatment for CML and a frequent indication for transplant, is in a steady decline given the impressive response rates and durable remissions achieved with TKIs.
In this chapter, we will provide a concise review for the role of allo-HCT in Philadelphia chromosome-negative MPNs and CML, with special focus on risk stratifications, indications of transplant, and progress in transplant strategies and transplant outcomes over the past two decades.
Staging and Prognostic Factors
Myelofibrosis
Several prognostic systems developed and validated over the past two decades to predict MF survival and/or to define high-risk subgroups who may benefit from transplant, and can be used in clinical trials to explore new therapeutics. Initial prognostic systems were solely based on clinical/biochemical features. The International Prognostic Scoring System (IPSS) is validated for MF risk stratification at time of diagnosis and is based on five factors including age, anemia, white blood cells (WBCs), and presence of constitutional symptoms and peripheral blood blasts ( Table 19.1 ). Four distinct risk groups can be identified based on the IPSS with median overall survival (OS) of 135 months for the low-risk group compared to only 27 months for those with high-risk disease. While IPSS is only applicable at diagnosis, the Dynamic IPSS (DIPSS) was later developed using the same risk factors but could be applied at any time during the follow-up of these patients (see Table 19.1 ). DIPSS was further refined (DIPSS-Plus) by incorporating three additional risk factors including red blood cell transfusion dependency, platelets, and cytogenetics (see Table 19.1 ). Several groups have since incorporated numerous molecular and mutational markers into their risk models, some of which rely exclusively on certain genetic and molecular markers such as the genetically inspired prognostic scoring system ( Table 19.2 ). Although these prognostic systems have important predictive value of whom to consider for transplant, they were not specifically designed to predict transplant outcomes. Furthermore, these prognostic systems are not yet well validated to use for post-PV and post-ET MF. The myelofibrosis transplant scoring system (MTSS) was developed more recently to determine primary and secondary MF prognosis after allo-HCT. The MTSS incorporated human leukocyte antigen (HLA) donor typing into other clinical/laboratory (age > 57 years, Karnofsky performance status < 90%, platelet count < 150 x 10 9 /L, WBCs > 25 x 10 9 /L) and molecular markers (ASXL1 mutation, non-CALR/MPL mutations) in 361 patients with MF and was able to stratify patients into four risk groups based on their estimated 5-year OS. The 5-year OS for patients with low-risk (score 0–2) was 83% compared to only 22% for those with very high-risk (score > 5) patients. The Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia-Prognostic Model (MYSEC-PM) risk model was developed for patients with post-PV and post-ET patients, and it does incorporate six poor risk factors including hemoglobin level < 11 g/dL, circulating blasts > 2%, CALR-unmutated genotype, platelet count < 150 x 10 9 /L, presence of constitutional symptoms, and increasing age. Four risk groups were distinguished based on the MYSEC-PM, with median survival not reached to low-risk group and was only 2 years for those with high-risk score [median follow-up was 3 (range, 0.6-27.3) years].
Table 19.1
IPSS, DIPSS, and DIPSS-Plus Prognostic Risk Scores for Myelofibrosis
| Risk Factor (Points) | ||
| IPSS | DIPSS | DIPSS-Plus |
| Age > 65 years (1) | Age > 65 years (1) | Intermediate-1 DIPSS (1) |
| WBC > 25 × 10 9 /L (1) | WBC > 25 × 10 9 /L (1) | Intermediate-2 DIPSS (2) |
| Hemoglobin <10 g/dL (1) | Hemoglobin < 10 g/dL (2) | High DIPSS (3) |
| Peripheral blood blast % ≥ 1 (1) | Peripheral blood blast % ≥ 1 (1) | Platelets < 100 x 10 9 /L (1) |
| Presence of constitutional symptoms (1) | Presence of constitutional symptoms (1) | Transfusion-dependent (1) |
| Unfavorable karyotype * (1) | ||
| Risk Group (Points) and Median Survival | ||
| IPSS | DIPSS | DIPSS-PLUS |
| Low (0), 11.3 years | Low (0 points), not reached | Low (0), 15.4 years |
| Intermediate-1 (1), 7.9 years | Intermediate-1 (1–2), 14.2 years | Intermediate-1 (1), 6.5 years |
| Intermediate-2 (2), 4 years | Intermediate-2 (3–4), 4 years | Intermediate-2 (2–3), 2.9 years |
| High (≥ 3), 2.3 years | High (5–6), 1.5 years | High (≥ 4), 1.3 years |
DIPSS , Dynamic International Prognostic Scoring System; IPSS , International Prognostic Scoring System; WBC , white blood cell
* Unfavorable karyotype includes the following: +8; −7/7q-; −5/5q-; i17q; 12p-; rearrangement 11q23
Table 19.2
MIPSS70, MIPSS70+, and GIPSS Prognostic Risk Scores for Myelofibrosis
| MIPSS70 | MIPSS70+ | GIPSS |
|---|---|---|
| Genetic Risk Factors (Points) | ||
| One HMR mutation (1) | One HMR mutation (2) | Type1/like CALR absent (1) |
| ≥ 2 HMR mutations (2) | ≥ 2 HMR mutations (2) | VHR karyotype (2) |
| Type1/like CALR absent (1) | Type1/like CALR absent (1) | Unfavorable karyotype (1) |
| VHR karyotype (4) | ASXL1, SRSF2, and/or U2AF1Q157 mutation (1 point each) | |
| Unfavorable karyotype (3) | ||
| Clinical Risk Factors (Points) | ||
| Hemoglobin < 10 g/dL (1) | Severe anemia * (2) | None |
| Leukocytes > 25 × 10 9 /l (2) | Moderate anemia * (1) | |
| Platelets < 100 × 10 9 /l (2) | Circulating blasts ≥ 2% (1) | |
| Circulating blasts ≥ 2% (1) | Constitutional symptoms (2) | |
| Constitutional symptoms (1) | ||
| Bone marrow fibrosis grade ≥ 2 (1) | ||
| Risk Group (Points) and Median Survival | ||
| MIPSS70 | MIPSS70+ | GIPSS |
| Low (0–1), not reached | Very low (0 points), not reached | Low (0), 26.4 years |
| Intermediate (2–4), 6.3 years | Low (1–2), 16.4 years | Intermediate-1 (1), 8 years |
| High (≥ 5), 3.1 years | Intermediate (3–4), 7.7 years | Intermediate-2 (2), 4.2 years |
| High (5–8), 4.1 years | High (≥3), 2 years | |
| Very high (≥ 9), 1.8 years | ||
GIPSS , Genetically-inspired prognostic scoring system; HMR , high molecular mutations, which include ASXL1 , SRSF2 , EZH2 , IDH1 , IDH2 for MIPSS70, and with 2AF1Q157 for MIPSS70+; MIPSS70, mutation-enhanced international prognostic system for transplant-age patients (age ≤ 70 years); MIPSS70+, mutation and karyotype-enhanced international prognostic system; VHR , very high risk karyotype
* Severe anemia is defined as hemoglobin < 8 g/dL in females and < 9 g/dL for males. Moderate anemia is defined as hemoglobin 8 to < 10 in females and 9 to < 11 for males.
Chronic Myeloid Leukemia
CML is characterized by three distinct clinical phases, CML in chronic phase (CP), accelerated phase (AP), and blast phase (BP). Over 85% of patients are diagnosed in the more indolent stage (CP), but if left untreated, most patients will eventually progress to an AP and BP. Despite the remarkable improvement in the prognosis of patients with CML-CP, it remains relatively poor for those in AP or BP. The Sokal and Hasford risk scores are frequently used to predict prognosis in CML-CP patients, based on clinical and laboratory features at diagnosis such as age, spleen size, platelet count, and blast percentage in peripheral blood; the Hasford score accounts additionally for peripheral blood eosinophils and basophils ( Table 19.3 ). The Sokal score has been shown to correlate with response to imatinib, with estimated OS at 54 months of 94%, 88%, and 81%, respectively, for low, intermediate, and high-risk Sokal score patients ( P < .01). The more recently introduced European Treatment and Outcome Study (EUTOS) and the EUTOS long-term survival scores are not commonly used in the United States. Clonal cytogenetic evolution while on treatment is one of the important poor risk factors, which is not accounted for in the aforementioned scores, particularly when it includes one of the “major route” abnormalities such as trisomy 8, trisomy 19, duplication of the Ph chromosome, and isochromosome 17q. Furthermore, the depth and timing of hematologic, cytogenetic, and molecular responses to TKIs correlate with prognosis.
Table 19.3
Sokal and Hasford Prognostic Risk Scores for Chronic Myeloid Leukemia
| Risk Category | Risk Index and Median Survival | |
|---|---|---|
| Sokal score * | ||
| EXP [0.0116 × (age − 43.4) + 0.0345 × (spleen size [cm below costal marigin] − 7.51) + 0.188 × [(platelet count/700)2 − 0.563] + 0.0887 × (myeloblasts − 2.1)]. | Low | < 0.8, 5 years |
| Intermediate | 0.8–1.2, 3.5 years | |
| High | > 1.2, 2.5 years | |
| Hasford score * | ||
| [0.666 when age ≥ 50 y + 0.042 × (spleen size [cm below costal marigin]) + 1.0956 (when platelet count ≥ 1500 × 109/L) + 0.0584 × myeloblasts + 0.2039 (when basophils ≥ 3%) + 0.0413 × eosinophils (%)]× 1000 | Low | ≤ 780, 98 months |
| Intermediate | 781–1480, 65 months | |
| High | > 1480, 42 months | |
* Sokal risk index was defined based on patients treated with conventional chemotherapy. Hasford risk index was defined based on patients treated with interferon-α–based regimens.
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