Oral Decitabine/Cedazuridine Is an Effective Ambulatory Therapy for Patients With Myelofibrosis Refractory to JAK2 Inhibitor Therapy.

BACKGROUND: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. METHODS: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024. RESULTS: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle. CONCLUSIONS: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

Updates on accelerated and blast phase myeloproliferative neoplasms: Are we making progress?

Management approaches for accelerated and blast phase myeloproliferative neoplasms remain challenging for clinicians and patients alike. Despite many therapeutic advances, outcomes for those patients who are not allogeneic haematopoietic cell transplant eligible remain, in general, very poor. Estimated survival rates for such blast phase patients is frequently reported as less than 6 months. No specific immunological, genomic or clinicopathological signature currently exists that accurately predicts the risk and timing of transformation, which frequently induces a high degree of anxiety among patients and clinicians alike. Within this review article, we provide an up-to-date summary of current understanding of the underlying pathogenesis of accelerated and blast phase disease and discuss current therapeutic approaches and realistic outcomes. Finally, we discuss how the horizon may look with the introduction of more novel agents into the clinical arena.

Treating accelerated and blast phase myeloproliferative neoplasms: progress and challenges.

Myeloproliferative neoplasms (MPNs) are a group of clonal hematologic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). MPNs are characterized by activating mutations in the JAK/STAT pathway and an increased risk of transformation to an aggressive form of acute leukemia, termed MPN-blast phase (MPN-BP). MPN-BP is characterized by the presence of ⩾20% blasts in the blood or bone marrow and is almost always preceded by an accelerated phase (MPN-AP) defined as ⩾10-19% blasts in the blood or bone marrow. These advanced forms of disease are associated with poor prognosis with a median overall survival (mOS) of 3-5 months in MPN-BP and 13 months in MPN-AP. MPN-AP/BP has a unique molecular landscape characterized by increased intratumoral complexity. Standard therapies used in de novo acute myeloid leukemia (AML) have not demonstrated improvement in OS. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy but is associated with significant morbidity and mortality and infrequently utilized in clinical practice. Therefore, an urgent unmet need persists for effective therapies in this advanced phase patient population. Here, we review the current management and future directions of therapy in MPN-AP/BP.

An Update on the Management of Advanced Phase Chronic Myeloid Leukemia.

PURPOSE OF REVIEW: While most patients with chronic myeloid leukemia (CML) present in a chronic phase and are expected to have a normal life expectancy, some patients present with or progress to a more aggressive accelerated phase (AP) or blast phase (BP) of CML. Herein, we discuss the diagnostic considerations of advanced phase CML and review its contemporary management. RECENT FINDINGS: Later-generation, more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib may result in superior outcomes in patients with advanced phase CML. For CML-BP, combination approaches directed against the blast immunophenotype appear superior to TKI monotherapy. The role of allogeneic stem cell transplantation is controversial in CML-AP but has consistently been shown to improve outcomes for patients with CML-BP. Advanced phase CML, particularly CML-BP, remains a poor risk subtype of CML. However, novel combination approaches using later-generation TKIs are being explored in clinical trials and may lead to improved outcomes.

[Clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm accelerated/blast phase].

Objective: To evaluate the clinical characteristics and prognostic factors of patients with Philadelphia-negative myeloproliferative neoplasm-accelerated phase/blast phase (MPN-AP/BP) . Methods: A total of 67 patients with MPN-AP/BP were enrolled from February 2014 to December 2021 at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Their clinical features and prognostic factors were analyzed retrospectively. Results: ① Sixty-seven patients with MPN-AP/BP with a median age of 60 (range, 33-75) years, including 31 males (46.3% ) and 36 females (53.7% ) , were analyzed. Forty-eight patients progressed from primary myelofibrosis (PMF) , and 19 progressed from other myeloproliferative neoplasms (MPNs) , which included polycythemia vera, essential thrombocythemia, and MPN unclassifiable. Patients who progressed from PMF had higher lactate dehydrogenase (LDH) levels than those who progressed from other MPNs (925.95 vs. 576.2 U/L, P=0.011) , and there were higher proportions of patients who progressed from PMF with splenomegaly (81.4% vs. 57.9% , P=0.05) , a myelofibrosis grade of ≥2 (93.6% vs. 63.2% , P=0.004) , and a shorter duration from diagnosis to the transformation to AP/BP (28.7 vs. 81 months, P=0.001) . ② JAK2V617F, CALR, and MPLW515 were detected in 41 (61.2% ) , 13 (19.4% ) , and 3 (4.5% ) patients, respectively, whereas 10 (14.9% ) patients did not have any driver mutations (triple-negative) . Other than driver mutations, the most frequently mutated genes were ASXL1 (42.2% , n=27) , SRSF2 (25% , n=16) , SETBP1 (22.6% , n=15) , TET2 (20.3% , n=13) , RUNX1 (20.3% , n=13) , and TP53 (17.2% , n=11) . The ASXL1 mutation was more enriched (51.1% vs. 21.1% , P=0.03) , and the median variant allele fraction (VAF) of the SRSF2 mutation (median VAF, 48.8% vs. 39.6% ; P=0.008) was higher in patients who progressed from PMF than those who progressed from other MPNs. ③ In the multivariate analysis, the complex karyotype (hazard ratio, 2.53; 95% confidence interval, 1.06-6.05; P=0.036) was independently associated with worse overall survival (OS) . Patients who received allogeneic stem cell transplantation (allo-HSCT) (median OS, 21.3 vs. 3 months; P=0.05) or acute myeloid leukemia-like (AML-like) therapy (median OS, 13 vs. 3 months; P=0.011) had significantly better OS than those who received supportive therapy. Conclusion: The proportions of patients with PMF-AP/BP with splenomegaly, myelofibrosis grade ≥2, a higher LDH level, and a shorter duration from diagnosis to the transformation to AP/BP were higher than those of patients with other Philadelphia-negative MPN-AP/BP. The complex karyotype was an independent prognostic factor for OS. Compared with supportive therapy, AML-like therapy and allo-HSCT could prolong the OS of patients with MPN-AP/BP.

First-line second generation tyrosine kinase inhibitors in patients with newly diagnosed accelerated phase chronic myeloid leukemia.

Accelerated phase (AP) CML at onset and have poorer prognosis than CP-CML. We hypothesize that off-license use of second generation TKI (TKI2) as front-line therapy might counterbalance this poor prognosis, with limited toxicity. In "real-life" conditions, newly diagnosed patients meeting the ELN cytological criteria for AP-CML or harboring ACA and treated with first-line TKI2 were included in this retrospective multicenter observational study. We enrolled 69 patients [69.5 % male, median age 49.5 years, median follow-up 43.5 months], segregated into hematologic AP [HEM-AP (n = 32)] and cytogenetically defined AP [ACA-AP (n = 37)]. Hematologic parameters were worse in HEM-AP [spleen size (p = 0.014), PB basophils (p < .001), PB blasts (p < .001), PB blasts+promyelocytes (p < .001), low hemoglobin levels (p < .001)]. Dasatinib was initiated in 56 % patients in HEM-AP and in 27 % in ACA-AP, nilotinib in 44 % and 73 % respectively. Response and survival do not differ, regardless of the TKI2: 81 % vs 84.3 % patients achieved CHR, 88 % vs 84 % CCyR, 73 % vs 75 % MMR respectively. The estimated 5-year PFS 91.5 % (95%CI: 84.51-99.06 %) and 5-year OS 96.84 % (95%CI: 92.61-100 %). Only BM blasts (p < 0.001) and BM blasts+promyelocytes (p < 0.001) at diagnosis negatively influenced OS. TKI2 as front-line therapy in newly diagnosed AP-CML induce excellent responses and survival, and counterbalance the negative impact of advanced disease phase.

Progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma and B-cell prolymphocytic leukemia: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: Session 3 of the 2021 Workshop of the Society for Hematopathology/European Association for Haematopathology examined progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B-cell prolymphocytic leukemia (B-PLL). METHODS: Thirty-one cases were reviewed by the panel. Additional studies such as immunohistochemistry and molecular genetic testing, including whole-exome sequencing and expression profiling, were performed in select cases. RESULTS: Session 3 included 27 CLL/SLL cases and miscellaneous associated proliferations, 3 cases of B-PLL, and 1 case of small B-cell lymphoma. The criteria for -accelerated CLL/SLL are established for lymph nodes, but extranodal disease can be diagnostically challenging. Richter transformation (RT) is a broad term and includes true transformation from original CLL/SLL clone(s) and clonally unrelated neoplasms. The morphologic, immunophenotypic, and genetic spectrum is diverse with classical and highly unusual examples. T-cell proliferations can also be encountered in CLL/SLL. B-cell prolymphocytic leukemia is a rare, diagnostically challenging disease due to its overlaps with other lymphoid neoplasms. CONCLUSIONS: The workshop highlighted complexity of progression and transformation in CLL/SLL and B-PLL, as well as diagnostic caveats accompanying heterogeneous presentations of RT and other manifestations of disease progression. Molecular genetic studies are pivotal for diagnosis and determination of clonal relationship, and to predict response to treatment and identify resistance to targeted therapy.

Accelerated and blast phase myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) have an inherent risk of transformation into blast phase (MPN-BP) or accelerated phase (MPN-AP) which is characterized by presence of ≥20% or 10-19% peripheral blood or bone marrow blasts, respectively. Primary myelofibrosis (PMF) is associated with the highest risk of blastic transformation (14.2%), followed by polycythemia vera (PV) (6.8%) and essential thrombocythemia (ET) (3.8%). Risk of leukaemic transformation (LT) in PMF can be determined by a three-tiered model based on presence of IDH1 mutation, circulating blasts ≥3%, SRSF2 mutation, age >70 years, ASXL1 mutation, and moderate/severe anemia with high, intermediate, and low risk groups (LT incidence 57%, 17%, and 8%, respectively). Currently, treatment of MPN-AP/BP includes acute myeloid leukaemia (AML)-like induction chemotherapy or hypomethylating agents alone or in combination with venetoclax and/or ruxolitinib. In transplant-eligible patients, our goal is to achieve complete remission with or without count recovery, before proceeding with allogeneic stem cell transplantation, which is the only modality associated with long-term survival. In the current review, we discuss our diagnostic, prognostic, and therapeutic approach to patients with MPN-AP/BP.

Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial.

BACKGROUND: BCR-ABL1T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP). METHODS: In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses. RESULTS: A total of 165 patients (> 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia. CONCLUSIONS: Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation. TRIAL REGISTRATION: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).

Chronic Myeloid Leukemia: Part II-Cost of Care Among Patients in Advanced Phases or Later Lines of Therapy in Chronic Phase in the United States from a Commercial Perspective.

Background: Tyrosine kinase inhibitors (TKIs) are the standard-of-care treatment for chronic myeloid leukemia in chronic phase (CML-CP). Despite advances in therapy, there remains a proportion of patients with CML-CP that are refractory/intolerant to TKIs, and these patients cycle through multiple lines of therapy. Moreover, even with TKIs, some patients progress to accelerated phase/blast crisis (AP/BC), which is associated with particularly poor clinical outcomes. Objectives: To describe real-world treatment patterns, healthcare resource utilization (HRU), and costs of patients with CML-CP reaching later lines of therapy or progressing to AP/BC in the United States. Methods: Adult CML patients from administrative claims data (January 1, 2000-June 30, 2019) were classified by health state: on third-line (CML-CP On Treatment), on fourth or later lines (CML-CP Post-Discontinuation), or progressed to AP/BC (CML-AP/BC). Outcomes were assessed by health state. Results: There were 296 (4620 patient-months), 83 (1644 patient-months), and 949 (25 593 patient-months) patients classified in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohorts, respectively. Second-generation TKIs (nilotinib, dasatinib, and bosutinib) were most commonly used in the CML-CP On Treatment (69.1% of patient-months) and CML-CP Post-Discontinuation cohorts (59.1% of patient-months). Three-month outpatient incidence rates (IRs) were 7.6, 8.3, and 7.0 visits in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $597 per service. Three-month inpatient IRs were 0.6, 0.7, and 1.4 days in the CML-CP On Treatment, CML-CP Post-Discontinuation, and CML-AP/BC cohort, respectively, with mean costs of $5892 per day. Mean hematopoietic stem cell transplantation cost was $352 333; mean 3-month terminal care cost was $107 013. Discussion: Cost of CML care is substantial among patients with CML reaching third-line, fourth or later lines, or progressing to AP/BC, suggesting that the disease is associated with a significant economic and clinical burden. From third-line to fourth or later lines, HRU was observed to increase, and the incidence of inpatient days was particularly high for those who progressed to AP/BC. Conclusion: In this study, patients with CML cycling through TKIs in later lines of therapy or progressing to AP/BC experienced substantial HRU and costs, suggesting unmet treatment needs.

Resurgence of myeloproliferative neoplasm in patients in remission from blast transformation after treatment with hypomethylating agents.

Subsequent blast (BP) or accelerated phase (AP) is a severe complication of Philadelphia-negative myeloproliferative neoplasms (MPNs). The prognosis is generally dismal, but hypomethylating agents (HMAs) may induce a long-lasting response in a minority of patients. Here, we report a cohort of six patients with BP/AP-MPN who experienced MPN relapse after a leukemia response was obtained with azacytidine. Five of the patients achieved complete remission despite the presence of characteristics associated with poor prognosis, such as complex and monosomal karyotypes, TP53 mutations, and EVI1 overexpression. These remissions persisted for over five years in four of the 6 patients. All patients showed rapid reemergence of MPN within a median of two months with thrombocytosis requiring the addition of anagrelide, hydroxyurea, or ruxolitinib given continuously in parallel with the azacytidine cycle. Serial JAK2 V617F allelic burden measurements showed little variation. Thromboembolic events occurred in 3 patients, one leading to death. These findings confirm that HMA may reverse the disease course in AP/BP-MPN to a more chronic phase that may last for years but also lead to morbidity and mortality. Combining maintenance therapy with HMA and MPN-specific drugs appears to be a possible approach to avoiding leukemia relapse and controlling MPN disease.

Mutational landscape of blast phase myeloproliferative neoplasms (MPN-BP) and antecedent MPN.

Myeloproliferative neoplasms (MPN) have an inherent tendency to evolve to the blast phase (BP), characterized by ≥20% myeloblasts in the blood or bone marrow. MPN-BP portends a dismal prognosis and currently, effective treatment modalities are scarce, except for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in selected patients, particularly those who achieve complete/partial remission. The mutational landscape of MPN-BP differs from de novo acute myeloid leukemia (AML) in several key aspects, such as significantly lower frequencies of FLT3 and DNMT3A mutations, and higher incidence of IDH1/2 and TP53 in MPN-BP. Herein, we comprehensively review the impact of the three signaling driver mutations (JAK2 V617F, CALR exon 9 indels, MPL W515K/L) that constitutively activate the JAK/STAT pathway, and of the other somatic non-driver mutations (epigenetic, mRNA splicing, transcriptional regulators, and mutations in signal transduction genes) that cooperatively or independently promote MPN progression and leukemic transformation. The MPN subtype, harboring two or more high-molecular risk (HMR) mutations (epigenetic regulators and mRNA splicing factors) and "triple-negative" PMF are among the critical factors that increase risk of leukemic transformation and shorten survival. Primary myelofibrosis (PMF) is the most aggressive MPN; and polycythemia vera (PV) and essential thrombocythemia (ET) are relatively indolent subtypes. In PV and ET, mutations in splicing factor genes are associated with progression to myelofibrosis (MF), and in ET, TP53 mutations predict risk for leukemic transformation. The advent of targeted next-generation sequencing and improved prognostic scoring systems for PMF inform decisions regarding allo-HSCT. The emergence of treatments targeting mutant enzymes (e.g., IDH1/2 inhibitors) or epigenetic pathways (BET and LSD1 inhibitors) along with new insights into the mechanisms of leukemogenesis will hopefully lead the way to superior management strategies and outcomes of MPN-BP patients.

Comparative Gene Expression Analysis Reveals Similarities and Differences of Chronic Myeloid Leukemia Phases.

Chronic myeloid leukemia (CML) is a slowly progressing blood cancer that primarily affects elderly people. Without successful treatment, CML progressively develops from the chronic phase through the accelerated phase to the blast crisis, and ultimately to death. Nowadays, the availability of targeted tyrosine kinase inhibitor (TKI) therapies has led to long-term disease control for the vast majority of patients. Nevertheless, there are still patients that do not respond well enough to TKI therapies and available targeted therapies are also less efficient for patients in accelerated phase or blast crises. Thus, a more detailed characterization of molecular alterations that distinguish the different CML phases is still very important. We performed an in-depth bioinformatics analysis of publicly available gene expression profiles of the three CML phases. Pairwise comparisons revealed many differentially expressed genes that formed a characteristic gene expression signature, which clearly distinguished the three CML phases. Signaling pathway expression patterns were very similar between the three phases but differed strongly in the number of affected genes, which increased with the phase. Still, significant alterations of MAPK, VEGF, PI3K-Akt, adherens junction and cytokine receptor interaction signaling distinguished specific phases. Our study also suggests that one can consider the phase-wise CML development as a three rather than a two-step process. This is in accordance with the phase-specific expression behavior of 24 potential major regulators that we predicted by a network-based approach. Several of these genes are known to be involved in the accumulation of additional mutations, alterations of immune responses, deregulation of signaling pathways or may have an impact on treatment response and survival. Importantly, some of these genes have already been reported in relation to CML (e.g., AURKB, AZU1, HLA-B, HLA-DMB, PF4) and others have been found to play important roles in different leukemias (e.g., CDCA3, RPL18A, PRG3, TLX3). In addition, increased expression of BCL2 in the accelerated and blast phase indicates that venetoclax could be a potential treatment option. Moreover, a characteristic signaling pathway signature with increased expression of cytokine and ECM receptor interaction pathway genes distinguished imatinib-resistant patients from each individual CML phase. Overall, our comparative analysis contributes to an in-depth molecular characterization of similarities and differences of the CML phases and provides hints for the identification of patients that may not profit from an imatinib therapy, which could support the development of additional treatment strategies.

Abnormal eosinophils with immature eosinophilic granules in chronic myeloid leukemia in accelerated phase.

Abnormal eosinophils with immature eosinophilic granules are typically observed in acute myeloid leukemia with inv (16) (p13.1q22) or t (16;16) (p13.1;q22) but can also be seen in chronic myeloid leukemia without inv (16) or t (16;16).

Accelerated Phase Chronic Myeloid Leukemia and Treatment Free Remission Maintained After Five Years of Nilotinib: A Case Report.

The present article reports the case of a patient presenting with chronic myeloid leukemia, diagnosed during the accelerated phase (>20% blasts in peripheral blood samples and megakaryocyte agglomerates in the bone marrow). The subject was treated with first-line therapy with the tyrosine kinase inhibitor nilotinib and reached complete clinical and molecular remission (according to the European Leukemia Net-ELN-criteria), which persisted over five years of treatment. Five years after discontinuation of nilotinib (ten years from diagnosis), the patient is in good clinical condition, with no traces of BCL-ABL1 at molecular evaluation (molecular response, MR5). The case is discussed in the setting of current literature, providing an overview on chronic myeloid leukemia and a discussion on treatment options available.

Accelerated Phase of Myeloproliferative Neoplasms.

BACKGROUND: Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of the cases. MPN-AP and MPN-BP are characterized by 10-19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival. SUMMARY: MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3-5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.

Accelerated and Blast Phase Myeloproliferative Neoplasms.

Accelerated and blast phase myeloproliferative neoplasms are advanced stages of the disease with historically a poor prognosis and little improvement in outcomes thus far. The lack of responses to standard treatments likely results from the more aggressive biology reflected by the higher incidence of complex karyotype and high-risk somatic mutations, which are enriched at the time of transformation. Treatment options include induction chemotherapy (7 + 3) as that used on de novo acute myeloid leukemia or hypomethylating agent-based therapy, which has shown similar outcomes. Allogeneic stem cell transplantation remains the only potential for cure.

Usefulness of the Sauvegrain Method of Bone Age Assessment in Indian Children.

INTRODUCTION: Bone age estimation is very useful in children undergoing epiphysiodesis or guided growth surgery especially during the years of accelerated growth. It may be noted that no data are available on bone age estimation for Indian children of this age group. Sauvegrain (French) method is a very useful and simple method for bone age assessment during the years of accelerated growth. We decided to check the usefulness and the accuracy of the Sauvegrain method in Indian children. MATERIALS AND METHODS: A team of two pediatric orthopaedic surgeons and a radiologist scored elbow X-rays of 80 healthy children (40 boys and 40 girls), using the Sauvegrain method twice. Interobserver reliability and intraobserver reproducibility of the Sauvegrain scoring were assessed. RESULTS: There was a very strong correlation between all observers in both rounds (r = > 0.8) and an excellent reproducibility by the same observer in both rounds (r = 0.955). Chronological and bone age are considered the same if the difference between them is less than 6 months. With this criterion bone and chronological ages matched in > 37% of boys and girls, similar to the study done in French children. In the nonmatching group, more children had delayed bone age compared to their chronological age. CONCLUSION: The Sauvegrain method of bone age assessment described for French children was found to be useful in estimating bone age in Indian children. It is especially helpful in the clinical practice for detecting mismatch between the chronological and the radiological age before undertaking guided growth or epiphysiodesis.