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Background Fatigue is distressing and affects quality of life (QoL) among patients with myelodysplastic syndrome (MDS), aplastic anemia (AA), and paroxysmal nocturnal hemoglobinuria (PNH). Limited data exist on the impact of fatigue, QoL, and related symptoms in these patients. Objective Prospectively assess fatigue (functional assessment of cancer therapy‐anemia [FACT‐An]); QoL (FACT‐An subscales); pain (brief pain inventory); and depression, anxiety, and stress (depression anxiety stress scale‐21) and strategies used to manage these symptoms in patients with MDS, AA, and PNH. Methods Surveys were administered via the AA and MDS International Foundation website and database from October 2014 through April 2015 in a cross‐sectional study. Results were summarized using descriptive statistics. Results Of 303 patients, 145 (48%) had MDS, 84 (28%) had AA, and 74 (24%) had PNH; 31 (10%) had >1 diagnosis. The mean age was 57 years, 200 (66%) were female, and 195 (92%) were white. The mean fatigue scores were 25 (range 1‐52) for the whole cohort, 28 for AA, 25 for MDS, and 24 for PNH (P = 0.117); these are all considered severe level. The mean QoL score was 68 (range 10‐104) for the whole cohort, 67 for AA, 69 for MDS, and 67 for PNH (P = 0.821). The ranges for stress were normal; pain and depression, mild; and anxiety, moderate. The most common management strategies perceived as helpful for fatigue in the past month were preserving energy, physical activity, and naps. Conclusions Many patients with MDS, AA, and PNH report severe fatigue. The helpfulness of fatigue management strategies may impact patients’ continued use; whether these strategies are beneficial and decrease fatigue levels needs more study.

Background: In patients with ALL, inability to receive L-asparaginase therapy due to hypersensitivity is associated with higher relapse risk (Gupta S, et al. J Clin Oncol. 2020). JZP458 is a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform to produce a reliable supply of enzyme with minimal immunologic cross-reactivity to E. coli-derived asparaginases. It has an amino acid sequence identical to that of native Erwinia asparaginase and its activity on asparagine is comparable based on in vitro measurements. This report includes initial analyses from the phase 2/3 open-label, multicenter, confirmatory pharmacokinetic (PK) and safety study (NCT04145531) of JZP458 in patients with ALL/LBL who developed hypersensitivity or silent inactivation to a long-acting E. coli-derived asparaginase. Methods: For eligible patients, each remaining course of long-acting E. coli-derived asparaginase was substituted by six doses of intramuscular (IM) JZP458 on a Monday/Wednesday/Friday (M/W/F) schedule. The primary efficacy endpoint of the trial was evaluated by the proportion of patients with the last 72-hr (primary endpoint) and last 48-hr (key secondary endpoint) nadir serum asparaginase activity (NSAA) level ≥0.1 IU/mL during the first treatment course. Cohort 1a started with 25 mg/m 2 IM JZP458 (M/W/F) and Cohort 1b explored a higher dose of 37.5 mg/m 2 IM M/W/F. A preliminary population pharmacokinetic (PPK) model using Cohort 1a and 1b data predicted that a regimen of 25 mg/m 2 (M/W) and 50 mg/m 2 (F) would be optimal to support M/W/F dosing and Cohort 1c was initiated using this regimen. Results: This initial report (data cutoff of Jan 11, 2021) provides data from 102 study patients enrolled in Cohort 1a (n=33, 51.5% male), 1b (n=53, out of 87 patients enrolled, 62.3% male), and 1c (n=16, out of 52 patients enrolled, 50.0 % male). The median (range) number of courses received in Cohorts 1a, 1b, and 1c as of the data cutoff was 4 (1, 14), 3 (1, 12), and 1 (1, 2), respectively, and 53% of patients were ongoing in treatment. The mean serum asparaginase activity (SAA) levels (95% confidence intervals [CIs]) for evaluable patients in Cohorts 1a, 1b, and 1c at 48 hrs were 0.4489 IU/mL (0.3720, 0.5258), 0.8376 IU/mL (0.6813, 0.9939), and 0.5085 IU/mL (0.3261, 0.6908); and at 72 hrs were 0.1543 IU/mL (0.1162, 0.1924), 0.3000IU/mL (0.2269, 0.3730), and 0.3579 IU/mL (0.2184, 0.4974). The proportion of patients achieving NSAA ≥0.1 IU/mL at 48 and 72 hr time points are presented in Table 1. PPK modeling and simulation analysis suggested that JZP458 given IM as 25 mg/m 2 on M/W and 50 mg/m 2 on F was expected to achieve NSAA levels ≥0.1 IU/mL in 99.8% of patients (95% CI: 99.6%, 100%) at 48 hours and 97.3% of patients (95% CI: 96.5%, 98.0%) at 72 hours. Grade 3 or higher treatment-emergent adverse events, regardless of causality, occurred in 73/102 (72%) patients. Adverse drug reactions (ADRs) are shown in Table 2. These ADRs are consistent with the safety profile observed with other asparaginases. Conclusions: The JZP458 IM dosing regimen of 25 mg/m 2 M and W, and 50 mg/m 2 F demonstrates a positive benefit:risk profile, achieving SAA levels ≥0.1 IU/mL in >90% of patients studied at both 48- and 72-hrs and a safety profile that is consistent with what has been observed in published literature on asparaginases. Figure 1 Figure 1. Disclosures Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Aoki: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zanette: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Agarwal: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Jazz Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Choi: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Servier Pharmaceuticals: Consultancy; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder.

Background T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL. Patients and methods We reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016. Results One hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin

The prognosis of patients with leukemia largely depends on the type of leukemia, clinical and pathologic prognostic factors of the leukemic cells, and patient characteristics. Over the past decade, long-term survival rates of patients with chronic myeloid leukemia (CML) have dramatically improved. On the other hand, these patients usually require life-long treatment, which may cause chronic physical, psychological, or socioeconomic complications that can affect patients’ well-being. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the United States. The natural history of CLL is generally indolent, with median survival durations of 10 years. Patients with CLL are at risk for secondary malignancies and infectious complications with disease- and treatment-related pathogenesis. Patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are generally treated with intensive chemotherapy, which may result in chronic symptoms that interfere with patients’ daily lives. Although some aspects of late or chronic toxic effects of treatment in patients with leukemia have been discussed, data concerning long-term effects remain limited. Further investigation is warranted to establish optimal monitoring schedules and effective interventions for survivors of adult-onset leukemia.

Background: T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell lymphoid leukemia. T-PLL is diagnosed based on characteristic immunophenotype, cytogenetic, and molecular aberrations (including members of the JAK-STAT signaling pathway) which may explain its aggressive clinical course. Cytogenetic features include chromosome (chr) 14 aberrations, accompanied by gene rearrangement involving proto-oncogenes TCL1 or MTCP1. In this analysis, we report our single-institution experience with T-PLL over the last 25 years. Methods: We reviewed the clinico-pathologic records of 101 consecutive patients (pts) with T-PLL, who presented to our institution between 1990 and 2015. The survival (OS) of pts was calculated from the date of initial presentation to the date of last follow up. Kaplan-Meier product limit method was used to estimate the median OS. Results: Median age of pts was 64 years (range 35-87 years). Eighteen pts (18%) presented with a performance status of 2 or higher. Lymphadenopathy, splenomegaly, skin lesions, hepatomegaly and pleural effusion were seen in 58%, 37%, 30%, 8%, and 7% of pts, respectively. Complex karyotype and aberrations in chr 14 were seen in 54 (63%) and 42 (49%) pts, respectively. TCL1 expression by immunohistochemistry was performed in 29 pts. The overexpression of TCL1 was detected in 23/29 pts (79%). Among untreated pts, 18/47 (38%) had a chr abnormality involving TCL-1. At initial presentation to our center, 59 pts (58%) were untreated and 42 pts (42%) had relapsed/refractory disease with a median of 2 prior treatments (range 1-6). Seventy-one pts (70%) were treated at our institution. Median overall OS from diagnosis in all pts was 21.7 mos (Range 1.5-107.7 mos). Median OS was longer in untreated pts than in pts with relapsed/refractory disease (27 mos vs. 17 mos; P=0.08). In a multivariate analysis for assessing the prognostic factors for OS in 43 untreated pts in whom all variables were available, we found that the presence of a pleural effusion HR (95% CI) 5.21 (1-27; P Conclusions: In this retrospective analysis, we have observed that outcomes in T-PLL remain poor. We have shown that alemtuzumab has some therapeutic activity in pts with T-PLL but durable remissions are uncommon. Rarity of this disease limits the conduct of large scale clinical trials; hence multicenter collaborative effort is required to conduct prospective studies. In pts who achieve a CR, consolidation treatment with SCT did not improve survival in our series. Studies to further define the genomic imbalances in pts with T-PLL and identify potential therapeutic targets and pathways providing drug resistance in T-PLL are underway. Table 1 Summary of treatment response and outcomes according to the type of therapy *Censored at stem cell transplant. Table 1. Summary of treatment response and outcomes according to the type of therapy. / *Censored at stem cell transplant. Figure (A-B) - Survival of pts after treatment with frontline therapy A) with/without stem cell transplantation after initial remission. B) With/without TCL-1 rearrangements. Figure. (A-B) - Survival of pts after treatment with frontline therapy A) with/without stem cell transplantation after initial remission. B) With/without TCL-1 rearrangements. Disclosures O'Brien: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Jain:Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Infinity: Research Funding; Incyte: Research Funding; BMS: Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Kantarjian:BMS, Pfizer, Amgen, Novartis: Research Funding.

Purpose of the review Epigenetic changes marked by DNA methylation are known to contribute to the malignant transformation of cells by silencing critical genes. Decitabine inhibits DNA methyltransferase and has shown therapeutic effects in patients with hematologic malignancies. However, the connection between the clinical activity of decitabine and its demethylating activity is not clear. Herein, we summarize the results of recent clinical trials of decitabine in hematologic malignancies, and review the translational research into decitabine's mechanism of clinical activity. Recent findings Low-dose decitabine has been studied recently in multiple clinical trials and has been shown to be effective for treatment of myelodysplastic syndromes. Correlative laboratory studies of clinical trials have shown that decitabine induces global hypomethylation as well as hypomethylation of gene-specific promoters and activation of gene expression. Past a given threshold, induction of higher degrees of hypomethylation is not directly associated with a better clinical outcome. Moreover, studies have suggested that patients with promoter hypermethylation of p15 INK4B at baseline have paradoxically a lower chance of achieving response than those without hypermethylation. Furthermore, several other genes activated by decitabine were independent of hypomethylation in the promoter regions. Conclusion While at least part of decitabine's activity is through induction of hypomethylation and reactivation of critical genes, mechanisms independent from hypomethylation are also important for decitabine's antitumor activity.

We previously reported that the hypermethylation of the p15INK4B gene promoter was frequently observed in myelodysplastic syndromes (MDS), and that it may be associated with disease progression. An unanswered question is whether p15INK4B gene methylation is restricted to undifferentiated blastic cells, or whether differentiated cells such as granulocytes or erythrocytes of MDS origin also harbor this epigenetic alteration. In this study, we analyzed the methylation status of the p15INK4B gene in MDS by the methylation-specific PCR (MSP) method, which is more sensitive than Southern blotting. The bone marrow mononuclear cells (BM-MNCs) of 23 MDS patients were analyzed, and six of them showed p15INK4B methylation. Progenitor assay with methylcellulose medium was also performed in all patients. In two of the six patients with p15INK4B-methylated BM-MNCs, erythroid and/or non-erythroid colonies formed were subjected to molecular analysis. Colonies with and without p15INK4B methylation were detected in both patients. Furthermore, X-chromosome inactivation (XCI) pattern of each colony was simultaneously determined by MSP-based human androgen receptor gene analysis (HUMARA-MSP), and all p15INK4B-methylated colonies showed the same XCI pattern, which was dominant among the colonies, while p15INK4B-unmethylated colonies showed both patterns of XCI, in each of the two patients. We then examined the methylation status of the p15INK4B gene of granulocyte (PB-PMN) fractions from 10 patients with available peripheral blood cells. In all four patients with p15INK4B-methylated BM-MNCs, their PB-PMNs showed p15INK4B methylation. These results suggest that p15INK4B methylation in hematopoietic cells in MDS patients is restricted to the MDS clone but not necessarily to blast cells.

Expression levels of DNA methyltransferase genes do not correlate with p15 INK4B gene methylation in myelodysplastic syndromes

Abstract 4457 Chronic myeloid leukemia (CML) is effectively treated with imatinib (IM), however, several mathematical models and ex vivo-examinations suggested that IM-therapy does not eradicate BCR-ABL-positive hematopoietic stem cells (HSC). We prospectively (0, 3, 6 and 12 months after IM-therapy) investigated 16 newly diagnosed and 22 long-term followed CML-chronic phase (CP) cases using methods previously reported (Jamieson et al., N Engl J Med, 2004. and Abe et al., Int J Hematol, 2008) (Figure 1) with FACSAria™ and quantitative RT-PCR of BCR-ABL among each sorted population; total mononuclear cells, HSC/Thy-1+, HSC/Thy-1–, common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP) and megakaryocyte erythroid progenitors (MEP). In optimal responders to IM-therapy, BCR-ABL transcripts in the HSC populations (HSC/Thy-1+ and HSC/Thy-1–) tended to be more retentive than other populations while gradual reduction was observed during the first 12 months in all populations. And discrepancy of minimum residual diseases (MRD) between the HSC populations and other populations was larger in patients after longer IM-therapy. In evaluating properties of CML stem cells and other markers, we observed irrelevant distribution of side population (SP) and expressions of ABC transporters (ABCB1 and ABCG2) in comparison with CD34/38 expression. We also prospectively investigated BCR-ABL transcripts in each population of 23 IM-resistant or -intolerant CML-CP cases and one newly diagnosed CML-accelerated phase (AP) case during treatment with second-generation tyrosine kinase inhibitors (2nd TKIs), dasatinib or nilotinib. Treatment with each inhibitor induced more rapid reduction of BCR-ABL transcripts even in the HSC population (CD34+CD38–) during the first 6 months and there was no significant difference of MRD among each population in optimal responders to 2nd TKIs-therapy. In the stromal co-culturing system using primary cells and leukemic NOD/SCID/IL2rgnull (NOG) mice xenotransplanted with Ph+ leukemia cells, retention of quiescent slow-cycling (Hoechst 33342low/Pyronin Ylow) CD34+ population after IM-treatment were observed and cell death mechanisms after treatment with 2nd TKIs are also under investigation. These results imply that therapy with 2nd TKIs could be a promising approach for quick and efficient reduction of the CML stem cells and cure of disease. Figure 1 Figure 1. Disclosures: Naoe: Kyowa-Kirin: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding.

Imatinib has remarkable activity in CML in all phases, with high rates of hematologic and cytogenetic response. However, in AP and BP responses are frequently less than complete hematologic remission (CHR), including partial hematologic remission (PHR) and return to chronic phase (second CP). The objective of this study was to investigate whether different responses to imatinib conferred a survival advantage in pts with CML in AP and BP. We evaluated 214 pts in AP and 76 pts in BP (11 lymphoid, 63 myeloid, 2 unclassified) treated with imatinib. Median age for AP pts was 49 yrs (range: 22–82 yrs) and for BP, 54 yrs (19–75 yrs). With a median follow-up of 49 months (1.9–67.5 months), 82 (38%) AP and 66 (87%) BP pts have died. A CHR and major cytogenetic (CG) response (MCR) have been achieved in 87% and 53% of AP pts, and 37% and 14% of BP pts, respectively. For AP pts the median overall survival (OS) and progression free survival (PFS) were 65 and 49 months, respectively. In BP pts, median OS and PFS were 7 and 3 months. The OS by best response to imatinib was as follows: Response No. (%) Median OS (months) p value Median PFS (months) p value CG CR=complete CG response (Ph=0%), CG PR=partial CG response (Ph We conclude that although cytogenetic responses confer the most survival advantage in AP and BP after imatinib therapy, hematologic responses are associated with a survival benefit.