Clinicopathologic Characteristic and Natural History of Patients with Non Hereditary, Non Polycythemia Vera (NH/NPV) Persistent Polycythemia

Abstract Introduction; Polycythemia Vera (PV), is one of the most common Philadelphia chromosome negative myeloproliferative disorders. The identification of Janus Kinase (JAK) 2 mutations and the publication of 2016 revision of WHO classification of myeloid neoplasms has improved diagnostic accuracy of PV. The lower cut-off values of Hemoglobin (Hb) and hematocrit (Hct) used in WHO diagnostic criteria, however, resulted in increased number of adult patients undergoing further evaluation for PV leading to identification of patients with acquired, idiopathic Persistent polycythemia (PP) who not meet WHO criteria for PV despite extensive work up. The clinicopathologic features, disease course, treatment and outcomes of these patients has not been well characterize. This study seeks to described clinicopathologic and molecular profile of cohort of adult patients with Non Hereditary, Non-Polycythemia Vera (NHNPV) Persistent Polycythemia. Methodology; Patients with PP diagnosed and followed up in Fresno community regional medical center/University of San Francisco (UCSF) Fresno, from January 2010 to December 2020 were reviewed. Patients who didn't meet WHO diagnostic criteria for PV after full evaluation including bone marrow biopsies were included in the study. Those with incomplete evaluation, clearly attributable secondary causes of polycythemia or erythropoietin (EPO) level above institutional laboratory reference range (2-18), were excluded from the study. Patients with polycythemia diagnosed at pediatric age were also excluded. The study was approved by institutional review board of UCSF Fresno. Results; 129 subjects with JAK 2 Negative PP were reviewed of which 63 had EPO levels within or below the normal range (2-18). Of 36 patients who met the study inclusion and exclusion criteria, majority were males (70% N= 28) and non-Hispanic (56% N=20) with median age at diagnosis of 48.5 years (range 18-70 years). Half of the patients (N=18) have no identifiable etiology of PP. In patients with associated conditions, the most common is non-oxygen requiring clinical OSA (36%) and tobacco smoking (19.4%). Of note, all these patients have EPO level less than 10 which represents the median value of the local institutional defined normal range for EPO. Four (11%) patients have non-iron overloaded hemochromatosis gene mutation (1 Homozygous H63D HFE gene, 2 heterozygous mutation and one with unspecified mutation type). Average Hb and Hct at diagnosis was (17.26+/- 2.23) and (49.76+/- 6.34) respectively. Mean EPO level 7.05+/-2.75 with less than third of patients 8 (22%) with level less or equal to in 5 units. There is no statistically significance difference between mean diagnostic EPO level between males and females in the study (7.20+/-2.89 vs.6.51+/-2.26) and so is the Hct though males have numerically higher levels. The most common bone marrow morphology includes normocellularity (51.76+/-10.36) with erythroid hyperplasia (25%) or megakaryocyte hyperplasia without dysplasia (17%) and grade 1/3 fibrosis 6/36. Abnormal mutations were identified in 17 patients whose bone marrow biopsies were evaluated with limited or extensive next generation sequencing (NGS). Of those patients with available results, 6 patients (35% out of those with NGS) have identifiable previously well described genetic mutations {FANCA S1311fs*1, HGF R134H, TP53 splice site 97-2A>G, KMT2A (Gain), MLL3 (KMT2C) and AFF4, ASXL1 c.1934dupG/TrpfsX12 (p. Gly646)}. 9 patients had variance of unknown significant (VUS) mutations (Table 1) with average of 6.2 mutation per patient. Only 1 VUS (TSC1 K587R) was reported in 2 different patients (#7, #9) Mild Myeloproliferative neoplasia (MPN) associated symptoms was reported in 22% of patient with Intermittent phlebotomy (72% N= 26) and aspirin (75% N=27) was the treatment for majority of patients. One patient died during the follow up period. No patient progressed to other MPN, myelofibrosis or AML during the study period. Conclusion; With improved diagnostic criteria and accuracy of PV, increased number of patients are diagnosed with NHNPV Persistent polycythemia. None of the mutation or VUS identified from extensive evaluation is recurrent in our cohort of patient. Longer follow up is needed to delineate clinical significance and prognosis of these mutation in patients with NHNPV persistent Polycythemia. Figure 1 Figure 1. Disclosures Abdulhaq: BMS, Alexion, Oncopeptides, Morphosys, Pfizer, Norvartis: Honoraria; Oncopeptides, Alexion, Amgen: Speakers Bureau; Morphosys, BMS, Amgen: Membership on an entity's Board of Directors or advisory committees.

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Severe Alterations of Bone Mass and Bone Structure after Allogeneic Stem Cell Transplantation: An Osteopathologic Analysis.

Blood ◽

10.1182/blood.v108.11.3025.3025 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3025-3025

Author(s):

Gero Massenkeil ◽

Cornelia Fiene ◽

Oliver Rosen ◽

Bernd Doerken ◽

Renate Arnold ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Bone Density ◽

Bone Mass ◽

Structural Changes ◽

Trabecular Thickness ◽

Bone Marrow Biopsies ◽

Number Of Patients ◽

Over Time

Abstract Prolonged survival after allogeneic SCT has led to an increased awareness of late complications in these patients. Loss of bone density after SCT has been reported in radiologic analyses (Ebeling 1999, Schulte 2000, Massenkeil 2001). We have studied bone mass and structure alterations in bone marrow biopsies after SCT. Patients and Methods: 67 patients after allogeneic SCT were included in this analysis. Median age was 36 years (range 17–56), 35 male, 32 female. Diagnoses were: ALL 27 patients, AML 14, MDS 6, CML 20. 38 patients were in 1. CR or 1. cP, 29 were transplanted with advanced disease. 64 received standard high-dose conditioning and 3 were transplanted after reduced intensity conditioning. 42 received bone marrow and 25 mobilized peripheral blood as stem cell source.40 patients were transplanted from HLA-identical related and 27 from unrelated donors. 31 bone marrow biopsies underwent Micro-CT (Scanco, Zürich, CH) and were analysed after 3-D reconstruction. Usual parameters of trabecular structure were investigated. Results: Median bone volume/tissue volume (BV/TV), which serves as a parameter of histopathologic bone mass was 13.7% before SCT (range 8.6–44.4%), well below 18%, which are considered the osteopathologic threshold for osteoporosis. At first follow-up 6–9 months after SCT, BV/TV had dropped to 10.1% (5.9–24.6%) and at 1–2 years after SCT BV/TV was still below the pre-SCT values at 12.2% (6.1–19.3%). Number of trabecules (Tb.N.) dropped from 1.63/mm (range 0.93–2.32/mm) to 1.34 (1.01–5.61/mm) after 6–9 months and slightly increased to 1.54 (1.26–1.88/mm) after 1–2 years. Trabecular thickness (Tb. Th.) fell from 0.20 mm before SCT (normal Tb. Th. 0.20–0.30 mm) (range 0.16–0.49 mm) to a minimum of 0.16 mm (0.14–0.25 mm). As a consequence, intertrabecular space (Tb.Sp., normal appx. 0.60 mm) increased from 0.60 mm (0.36–1.11 mm) to 0.73 mm (0.23–1.04 mm) after SCT. Discussion: Independently from underlying diagnosis trabecular parameters changed within the first 6 months after SCT, indicating early loss of bone mass and structure. Afterwards, they showed some tendency to normalization, however, none of the parameters went back to baseline values. Number of patients analysed over time was to small to find out causative clinical parameters like chronic GvHD. Radiologic bone density was available for these patients and showed synchronous variations over time. Conclusions: Structural changes of trabecular bone develop early after allogeneic SCT and underscore the severeness of bone loss observed in these patients. Even after prolonged follow-up, structural changes and diminished bone mass persist and indicate a long-term cause of morbidity in these patients.

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Treatment of hairy cell leukemia with alternating cycles of pentostatin and recombinant leukocyte A interferon: results of a phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.4.721 ◽

1990 ◽

Vol 8 (4) ◽

pp. 721-730 ◽

Cited By ~ 22

Author(s):

A Martin ◽

S Nerenstone ◽

W J Urba ◽

D L Longo ◽

J B Lawrence ◽

...

Keyword(s):

Bone Marrow ◽

Hairy Cell Leukemia ◽

Pathologic Complete Response ◽

Hairy Cell ◽

Cell Leukemia ◽

Cell Infiltrate ◽

Recombinant Interferon ◽

Bone Marrow Biopsies ◽

Hairy Cells

Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; dCF) (4 mg/m2 intravenous [IV] every week x 3) and recombinant interferon-alpha 2a (rIFN-alpha 2a) (3 x 10(6) units subcutaneously [SC] daily x 4 weeks) in alternating months for a total of 14 months. Eleven patients had undergone splenectomy; four had received prior systemic therapy with chlorambucil and/or steroids. All 15 are evaluable for toxicity and peripheral blood response, while 14 are assessable for bone marrow response. Toxicity was tolerable with grade 3 or 4 nausea and vomiting in three patients, neutropenic fevers in five, transient but significant depression in eight, and localized cutaneous herpes zoster in four. Circulating hairy cells were undetectable by the end of the first month in 10 of 13 patients, and by the end of the second month in the other three. Fourteen patients had bilateral bone marrow biopsies performed at baseline after 6 months of treatment, at the end of treatment (14 months), and at 6-month intervals during follow-up. Before treatment, all patients had hypercellular marrows with hairy cels replacing normal marrow elements; all showed at least a 95% clearing of their hairy cell infiltrate by 6 months of therapy. However, small collections of residual hairy cells could be detected intermittently on at least one side of bilateral samples in all patients. All patients have completed treatment with a median duration of follow-up off therapy of 27 months (range, 15 to 31 months). To date, all peripheral counts and serum soluble interleukin-2 receptor (sIL2R) levels remain stable, and no patient has had progression of the hairy cell infiltrate in the bone marrow. Although no patient achieved a pathologic complete response, alternating monthly cycles of dCF and rIFN-alpha 2a produced durable partial remissions (PRs) in all patients. Continued follow-up is required to determine the length of such remissions.

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Clinical Relevance of Bone Marrow Biopsy in Staging and Follow-Up of Breast Cancer

Tumori Journal ◽

10.1177/030089168306900210 ◽

1983 ◽

Vol 69 (2) ◽

pp. 143-150 ◽

Cited By ~ 2

Author(s):

Giorgio Cruciani ◽

Gian Maria Fiorentini ◽

Giovanni Rosti ◽

Amelia Tienghi ◽

Daniele Bardella ◽

...

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Bone Metastases ◽

Bone Marrow Biopsy ◽

Clinical Relevance ◽

Bone Biopsy ◽

Bone Marrow Biopsies ◽

Female Patients

Bone marrow biopsies by Jamshidi needle were performed in 106 breast cancer female patients. Sixty-four of them were in follow-up after mastectomy, and neoplastic involvement of marrow was found in 21 patients (32.8%). Among the 42 women undergoing staging before mastectomy, the incidence of marrow involvement was 11.9% (5 women, all with radiographic positivity). Of the 37 women, either in follow-up or in the staging phase, with bone metastases detected by roentgenographic and isotopic examination, the bone biopsy was positive in 23 (62.1%), and 7 histologically had micrometastases. Three women, without any radiographic or isotopic sign of metastases, had positive biopsies. A good correlation was found between the hydroxyproline:creatinine ratio and neoplastic involvement of bone marrow.

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Cognitive Functions in Repeated Glioma Surgery

Cancers ◽

10.3390/cancers12051077 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1077

Author(s):

Gabriele Capo ◽

Miran Skrap ◽

Ilaria Guarracino ◽

Miriam Isola ◽

Claudio Battistella ◽

...

Keyword(s):

Cognitive Functions ◽

Inferior Frontal Gyrus ◽

Insular Cortex ◽

Malignant Degeneration ◽

Low Grade ◽

Normal Range ◽

Glioma Surgery ◽

Number Of Patients ◽

Significant Difference

Low-grade gliomas (LGG) are slow-growing brain tumors infiltrating the central nervous system which tend to recur, often with malignant degeneration after primary treatment. Re-operations are not always recommended due to an assumed higher risk of neurological and cognitive deficits. However, this assumption is relatively ungrounded due to a lack of extensive neuropsychological testing. We retrospectively examined a series of 40 patients with recurrent glioma in eloquent areas of the left hemisphere, who all completed comprehensive pre- (T3) and post-surgical (T4) neuropsychological assessments after a second surgery (4-month follow up). The lesions were most frequent in the left insular cortex and the inferior frontal gyrus. Among this series, in 17 patients the cognitive outcomes were compared before the first surgery (T1), 4 months after the first surgery (T2), and at T3 and T4. There was no significant difference either in the number of patients scoring within the normal range between T3 and T4, or in their level of performance. Further addressing the T1–T4 evolution, there was no significant difference in the number of patients scoring within the normal range. As to their level of performance, the only significant change was in phonological fluency. This longitudinal follow-up study showed that repeated glioma surgery is possible without major damage to cognitive functions in the short-term period (4 months) after surgery.

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P663 Efficacy of tofacitinib in patients with ulcerative colitis after previous ineffective biological therapies

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.791 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S545-S546

Author(s):

M Rutka ◽

K Farkas ◽

D Pigniczki ◽

K Szántó ◽

B Anita ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Response ◽

Induction Therapy ◽

Dose Escalation ◽

Real Life ◽

Janus Kinase ◽

Inadequate Response ◽

Mayo Score ◽

Number Of Patients

Abstract Background Tofacitinib (TFC) is an oral, small-molecule Janus kinase inhibitor, which was recently approved for moderate to severe ulcerative colitis (UC). The aim of the current real-life study was to determine efficacy of TFC induction therapy regarding the clinical response and remission in patients with active UC. We evaluated short-term efficacy data in a Hungarian cohort with prior exposure to other biological agents such as anti-TNF drugs and vedolizumab. Methods In this single-centre retrospective study, patients with TFC introduction were included. Since January 2019, a total of 16 patients received an oral TFC induction therapy in a dose of 10 mg twice daily for 8 weeks. Endoscopic activity was evaluated by endoscopic Mayo (eMayo) score before the introduction of TFC and in case of an inadequate therapeutic response to the 5-mg-therapy to confirm therapeutic decision-making. Based on the evaluation of clinical symptoms and laboratory parameters, we either kept the dosage or reduced the dose to 5 mg according to local regulations. We also collected data from the 16. and 24. weeks of the therapy. Primary endpoints were a clinical response (as a reduction in partial Mayo Score [pMayo] by minimum 3 points) or remission (as a Mayo score of the maximum of 2 points and without blood in stool) at week 8. Results Sixteen patients had received the induction therapy (mean age: 36 years, 7 males and 9 females) in our centre. After 8 weeks, 12 (75%) patients responded to the TFC induction therapy and 6 (37.5%) of them were in remission. Four patients were primary non-responders (25%). Corticosteroid therapy (18 ± 7 mg) was required during the induction in 4 responder cases, which could be stepped down by week 8. As a continuous maintenance therapy, 4 patients have already reached the 16th week and 8 have completed the 24th week. By the end of the follow-up, 12 patients responded and 10 was in remission. During the observation period, 3 patients had to remain on 10 mg TFC dose, 6 patients required dose escalation from 5 mg to 10 mg and 5 mg was sufficient in case of only 3 patients after the introduction. Endoscopic activity showed a moderate decrease from 2.5 ± 0.5 eMayo score to 2 ± 1 (n = 7) until week 16. In respect the responder patients, CRP levels decreased from the mean of 7.23 to 5.02. No serious side-effects were observed during the follow-up. Conclusion After the 8-week TFC induction therapy, the response rate was high and only every fourth patients were non-responder. A low number of patients had adequate reactions to the 5 mg-therapy after the introduction, but TFC is effective with dose-escalation in respect of clinical response and remission in patients with UC, who have had an inadequate response to previous biological therapy.

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Correlation of Hemophagocytosis with Clinical Criteria of Hemophagocytic Lymphohistiocytosis and Recommendations for Screening Bone Marrow Samples in Adult Patients

Blood ◽

10.1182/blood-2020-139246 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-38

Author(s):

Caroline Wilson ◽

Wei-i Lee ◽

Matthew Cook ◽

Lillian Smyth ◽

Dipti Talaulikar

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Hemophagocytic Lymphohistiocytosis ◽

Research Funding ◽

Interobserver Variability ◽

Laboratory Data ◽

Adult Patients ◽

Advisory Committees ◽

Bone Marrow Biopsies ◽

Immunohistochemical Stain

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare condition resulting from a dysregulated inflammatory response. It can prove difficult to diagnose and portends a poor prognosis. Bone marrow (BM) biopsy is an easily accessible test that is often used to identify the presence of hemophagocytosis and assess for underlying malignancy. Currently there are no evidence-based guidelines on the reporting of hemophagocytosis on BM biopsy and no reports of a correlation between hemophagocytosis with the clinical diagnostic criteria for HLH. We therefore aimed to assess if the amount of hemophagocytosis identified in the BM biopsy correlates with HLH-2004 criteria. Secondary aims were to evaluate inter-observer variability in reporting hemophagocytosis, and to formulate recommendations for screening in BM specimens. Method A retrospective review of bone marrow biopsies from adult patients under investigation for HLH was undertaken independently by 2 hematopathologists who were blinded to the original biopsy report. Relevant clinical and laboratory data was extracted from medical records. The average number of actively hemophagocytic cells in each slide prepared from BM aspirates were quantified into 0, 1, 2-4 and ≥5. On trephine samples, hemophagocytosis was reported as either 'present' or 'absent', with the assistance of the CD68 immunohistochemical stain. Cases with discordance pertaining to the degree of hemophagocytosis were reviewed by both assessors to reach a consensus. Results Sixty-two specimens from 59 patients were available for assessment. An underlying hematological condition was identified in 34 cases (58%). The most common underlying hematological condition was lymphoma, found in 15 cases (25%). There was a significant association between the amount of hemophagocytosis identified on the aspirate samples and the number of HLH-2004 criteria met (p<0.05). In patients where hemophagocytosis was present (n=31), there was a significant correlation between the amount of hemophagocytosis and ferritin levels (p<0.05). Interobserver variability was present in 63% of cases. Based on our review, we make the following recommendations for reporting of hemophagocytosis in the BM samples:> 1. Count only macrophages ingesting intact hemopoietic cells. W2. Quantify the average number of active histiocytes per aspirate slide. W3. Count histiocytes away from particles where the cellular outline is clear. W4. Avoid counting conglomerates of histiocytes where the cellular margins are indistinct W5. On the aspirate specimen, assess for hemophagocytosis on both the trail and squash preparations. W6. Delineating hemophagocytosis on trephine samples is difficult without the use of a CD68 immunohistochemical stain. Interestingly, a study by Ho et al found no association between the BM histologic findings and the probability of hemophagocytosis (Ho et al, American Journal of Clinical Pathology, 2014). This difference highlights the need for standardised reporting of BM specimens. Conclusion Our findings indicate that the amount of hemophagocytosis present on BM samples correlates with the number of HLH-2004 criteria met. We found marked interobserver variability which we anticipate can be rectified with our recommendations on the reporting of hemophagocytosis. Disclosures Talaulikar: Takeda: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Cytoreductive Therapeutic Approach in the Essential Thrombocythemia (ET) Patients of the Registro Italiano Trombocitemia (RIT): Preliminary Data

Blood ◽

10.1182/blood.v112.11.5248.5248 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5248-5248

Author(s):

Luigi Gugliotta ◽

Alessia Tieghi ◽

Anna Candoni ◽

Monia Lunghi ◽

Gianluca Gaidano ◽

...

Keyword(s):

Bone Marrow ◽

Essential Thrombocythemia ◽

Therapeutic Approach ◽

Jak2 V617f ◽

Bone Marrow Biopsies ◽

Thrombotic Risk ◽

Significant Difference ◽

Cytoreductive Treatment ◽

Wbc Count

Abstract Background: the Registro Italiano Trombocitemia, that is a GIMEMA project, has been activated to registry Italian Essential Thrombocythemia (ET) patients, to improve the diagnosis appropriateness (WHO criteria), to verify the prognostic value of the clinical and biological parameters, to evaluate the compliance to the therapeutical Italian guidelines (1), and to create a network for activation of new studies. Objective: this analysis is mainly devoted to describe the ET patients registered in the RIT and to evaluate the therapeutic approach adopted in the 102 participating hematological centers. Material and methods: two thousand and fifteen ET patients have been registered after the written informed consent was obtained, and data validation by various expert panels is in progress. This preliminary report considers 1785 patients, diagnosed mainly (1078, 60.4%) since the publication in the year 2004 of the ET therapy Italian guidelines (1). Results: the patients, 678 (38%) males and 1107 (62%) females, showed at diagnosis: age 60.3 ± 16.8 years with higher values in males than in females (61.7 ± 15.3 vs. 59.4 ± 17.7, p<0.05), being the patients below 40 years 14% and those over 70 years 33% of cases; PLT count (109/L) 846 ± 309 with lower values in males than in females (813 ± 261 vs. 866 ± 334, p<0.002), and with values 1001–1500 and over 1500 in 16% and 4% of cases, respectively; WBC count (109/L) 9.1 ± 2.9, without difference by sex, and with values 12–15 in 10% and over 15 in 3% of cases; Hgb (g/dL) 14.2 ± 1.6 with higher values in males than in females (14.8 ± 1.5 vs. 13.8 ± 1.5, p<0.001), and with values over 16.5 in 8.5% of males and 2.7% of females, respectively; splenomegaly in 488 (27%), echo-documented in 324 cases (18%); history of hemorrhage and thrombosis in 90 (5%) and 325 (19%) of cases, respectively; disease-related symptoms in 41% and general thrombotic risk factors in 93% of cases, respectively. The WHO 2001 diagnostic criteria were reported for 33% of cases observed before the year 2004 and for 53 % of cases observed since the year 2004. Detailed data at diagnosis were reported as follows: bone marrow biopsy in 1087 cases (61%) with a frequency of 51% and 68% before and since the year 2004, respectively; bcr-abl study in 1045 cases (59%); cytogenetics in 828 cases (46%) with karyotype abnormalities in 27 patients (3%). The JAK2 V617F mutation, searched in 574 cases (32%), was observed in 320 of them (56%). The patient follow-up was 4.5 ± 4.5 years with a total of 5245 pt-yrs. During the follow-up the hemorrhagic events were 5.7% (1.3/100 pt-yrs), being the major events 1.9% (0.4/100 pt-yrs); the thrombotic complications were 14.9 % (3.3/100 pt-yrs), resulting the major arterial 9.4% (2.1/100 pt-yrs), the major venous 3.5% (0.8/100 pt-yrs) and the minor thrombosis 2% (0.4/100 pt-yrs). An antiplatelet treatment, almost always with low dose aspirin, was performed in 75% of the patients, without significant difference in the cases diagnosed before and since the 2004. A cytoreductive treatment was done with use of Hydroxyurea (HU, 64%), Interferon alpha (IFN, 16%), Anagrelide (ANA, 15%), Busulfan (BUS, 4%), and Pipobroman (PIPO, 2 %). In the ET patients diagnosed since the year 2004 respect those diagnosed before, it was observed a decrease in the use of all the cytoreductive drugs, particularly BUS (−62%), IFN ((−62%), and ANA ((−68%). The use of the cytoreductive drugs was related to the patient mean age (years): BUS (76), PIPO (72), HU (67), ANA (53), IFN (48). In the patients diagnosed since the 2004 as compared with those before 2004, the mean age of the treated patients increased for BUS (from 69 to 81 yrs, p<0.001) and for HU (from 64 to 69 yrs, p<0.001) while it decreased for IFN (from 49 to 46 yrs, p<0.05). Conclusion: in the analyzed patients of the ET Italian registry the diagnosis appropriateness resulted improved in the cases observed since the year 2004 respect those observed before, with an increase of bone marrow biopsies from 51% to 68% of patients. Moreover, in accord with the ET therapy Italian guidelines, the use of the cytoreductive drugs was less frequent in the patients diagnosed since the year 2004 than before (particularly for BUS, IFN, and ANA) and the more safe molecules IFN and ANA were preferentially deserved to the younger patients.

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Stable Long-Term Risk of Leukemia in Patients with Severe Congenital Neutropenia Maintained On G-CSF Therapy.

Blood ◽

10.1182/blood.v114.22.3206.3206 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3206-3206 ◽

Cited By ~ 1

Author(s):

Philip S. Rosenberg ◽

Cornelia Zeidler ◽

Audrey Anna Bolyard ◽

Blanche P. Alter ◽

Mary Ann Bonilla ◽

...

Keyword(s):

Bone Marrow ◽

Cumulative Incidence ◽

Bone Marrow Failure ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Hazard Curve ◽

Number Of Patients ◽

Increasing Trend

Abstract Abstract 3206 Poster Board III-143 BACKGROUND G-CSF therapy reduces sepsis mortality in patients with severe congenital neutropenia (SCN), but effective therapy has revealed a high syndromic predisposition to myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), particularly in patients who require higher doses of G-CSF. Although the long-term risk of MDS/AML after 10 or more years on therapy remains uncertain, prior data on the limited number of patients with long-term follow-up suggested the hazard rate might be as high as 8%/year after 12 years on G-CSF. METHODS We updated prospective follow-up of 374 well-characterized patients with SCN on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (Blood. 2006 Jun 15; 107(12):4628-35). We ascertained event-free time, deaths from sepsis, and MDS/AML events that accrued since our previous report. Follow-up was censored for patients who received a bone marrow transplant. RESULTS The update yielded 3590 person-years of follow-up versus 2043 in the prior report; among patients treated for 10 or more years, there were 849 person-years versus just 67 previously. In all, there were 61 MDS/AML events and 29 deaths from sepsis, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of death from sepsis remained qualitatively stable, at 0.81%/year (95% Confidence Interval, CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate. However, in contrast to the prior estimate that showed a subsequent increasing trend over time (with a large margin of error), the updated hazard curve attained a plateau: after 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year). Although this aspect of the natural history appears less dire than first suggested, after 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for death from sepsis and 22% (95% CI: 17 – 28%) for MDS/AML. Furthermore, for the subset of patients who failed to achieve at 6 months an absolute neutrophil count at or above the median value for the cohort (2188 cells/μL) despite doses of G-CSF at or above the median (8 μg/kg/day), the cumulative incidence after 15 years on G-CSF was 18% (95% CI: 7 – 28%) for death from sepsis and 34% (95% CI: 21 – 47%) for MDS/AML. With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold (95% CI: 1.08-1.43-fold) per doubling of the dose of G-CSF). CONCLUSIONS For SCN patients maintained on G-CSF therapy, the hazard of MDS/AML over the long-term falls significantly below the range suggested by preliminary data. The updated hazard estimate of 2.3%/year after 10 years on G-CSF (which includes both MDS and AML events) is similar to that for other inherited bone marrow failure syndromes with a high intrinsic risk of AML, notably Fanconi anemia and dyskeratosis congenita. Nonetheless, the cumulative incidence of both MDS/AML and sepsis death rises to very high levels, and the data continue to support the hypothesis that SCN patients with higher G-CSF requirements are also at higher risk of leukemia. Disclosures Boxer: Amgen Inc.: Equity Ownership. Dale:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speaker.

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Significance of Bone Marrow Karyotype and Morphology in Patients with Inherited Bone Marrow Failure Syndromes,

Blood ◽

10.1182/blood.v118.21.3431.3431 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3431-3431

Author(s):

Neelam Giri ◽

Blanche P Alter ◽

Helkha Peredo-Pinto ◽

M. Tarek Elghetany ◽

Irina Maric ◽

...

Keyword(s):

Bone Marrow ◽

Disease Progression ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Myelogenous Leukemia ◽

Monosomy 7 ◽

Cytogenetic Abnormalities ◽

Bone Marrow Failure Syndromes ◽

Number Of Patients

Abstract Abstract 3431 Recurring clonal cytogenetic abnormalities have been described in patients with Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS). In FA, gains of 3q and monosomy 7 (−7) imply progression to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In SDS, isochromosome 7q and deletion (del) 20q are usually benign. Dyskeratosis congenita (DC) and Diamond-Blackfan anemia (DBA) do not have unique clones. We report here the types and frequencies of cytogenetic clones and their association with morphologic MDS or AML in the major inherited bone marrow failure syndromes (IBMFS), in a prospective/ retrospective study of patients with FA, SDS, DC and DBA enrolled in the NCI IBMFS cohort from 2002–2010. Bone marrow (BM) morphology and cytogenetics (G-banding; selected FISH, CGH, SKY) performed at our institute and all outside cytogenetics reports were centrally reviewed. Cytogenetic abnormalities were defined and karyotypes designated according to ISCN (2009). Two independent blinded hematopathologists reviewed BM morphology. Diagnosis of morphologic MDS was based on a modification of WHO 2008 and required ≥10% dysplasia in 2 cell lineages. Data analysis was both cross-sectional and longitudinal. P values are global comparing all 4 disorders using Fisher's exact test.ParameterAll IBMFSFASDSDCDBAP valueTotal number (N)12835113646–N with clone ever2817 (49%)4 (36%)4 (11%)3 (7%)<0.01N with MDS ever105 (14%)3 (27%)1 (3%)1 (2%)0.01N with clone + MDS75 (14%)2 (18%)00<0.01N with clone alone2112 (34%)2 (18%)4 (11%)3 (7%)<0.01N with MDS alone301 (9%)1 (3%)1 (2%)0.3N with clone at 1st BM179 (26%)4 (36%)3 (8%)1 (2%)<0.01N with clones at follow-up118012<0.01N with follow-up BMs591791716–Median follow-up in years3 (0–19)6 (1–16)2 (1–6)3 (0–19)2 (0–10)– More FA and SDS patients had clones and/or MDS compared with DC or DBA (Table). MDS was always associated with clones in FA but not in the other IBMFS. In FA, bone marrow transplant (BMT) or death occurred with similar frequencies in those with or without clones. Among 17 patients with clones, follow-up cytogenetics were unavailable in 5; of these, 2 with clone alone [one with del 7q and 18p and one with t(3;6)(q?25;p?21)] progressed to AML, while one with clone and MDS died from other causes. Recurring abnormalities in 12 FA patients with clones followed for up to 16 years, included gains of 1q in 4, −7 or del 7q in 3, and deletions of 6p, 13q, 18p and 20q in 2 patients each; only one had gain of 3q. These patients showed fluctuation or disappearance of clones, new appearance of clones, stable clone, or clonal evolution. Progression to MDS occurred with gain of 1q and 6p deletion, gain of 3q, or −7 in 3 patients, respectively; one patient with MDS had clonal persistence. No disease progression was seen in 5 FA patients with clone alone. All 5 SDS patients with clones and/or MDS are alive with no disease progression. The 4 with a clone had stable persistent del 20q as a sole abnormality; 2 had MDS and 2 did not. One had MDS with a normal karyotype. Four DC patients had abnormal clones including 2 with gain of 1q only. One patient with 1q gain died from pulmonary fibrosis. Three others are alive; 2 with stable clones at 7 and 19 years' follow-up, respectively. One additional DC patient has morphologic MDS but no clone. All 3 DBA patients with clones had del 16q, 2 alone and 1 with del 9p; none had MDS. The clones were transient in 2, disappearing within 1–2 years; the third was recently identified. None of these had disease progression. One patient with morphologic MDS alone died from complications of iron overload. This study shows that clonal chromosome abnormalities occur more frequently in FA and SDS than in DC and DBA. Gain of 3q in FA was not as common here as reported by others. This is the first comprehensive study of clones and MDS in DC and DBA. Strengths of this study include the large number of patients, and central review of cytogenetics and morphology. It is unbiased compared with FA literature reports that include many patients referred for BMT. Limitations include a relatively small number of patients with each diagnosis and short follow-up in most. The study demonstrates that clones may fluctuate or disappear, and may not per se portend a bad prognosis. Progression to clinically significant MDS or AML may be related to the severity of cytopenias and not to clone alone, and warrants more extensive long-term studies. Disclosures: No relevant conflicts of interest to declare.

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Isolated Chromosome 20q Deletions in Patients with Non-Myeloid Disorders

Blood ◽

10.1182/blood.v120.21.1442.1442 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1442-1442

Author(s):

Dean Andrea ◽

Melissa Hayden ◽

Kathleen W. Rao ◽

Yuri D. Fedoriw ◽

Bahjat Qaquish ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Clinical Evidence ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Red Blood Cell Transfusion ◽

Bone Marrow Biopsies ◽

Chromosome 20 ◽

Dose Modifications

Abstract Abstract 1442 Background: Deletions of the long arm of chromosome 20 have conventionally been associated with myeloid neoplasms. The frequency of chromosome 20q deletion (del(20q)) is 1–10% in myeloid diseases and associated with good prognosis in patients with myelodysplastic syndromes (MDS) and poor response to treatment in patients with acute myeloid leukemia (Greenberg 1997; Campel 1994). Previously chromosome 20q deletions were thought to be pathognomonic for myelodysplastic syndrome. Due to the observation that del(20q) may be present in non-malignant clones in patients with non-myeloid cancers, the 2008 WHO Classification (Swerdlow ed.) stated that MDS could not be diagnosed solely on the basis of isolated del(20q). The significance of isolated del(20q) in non-myeloid disorders have yet to be defined. When this chromosomal abnormality is found incidentally in marrows of patients for non-myeloid cancers, some oncologist may consider altering plans for cytotoxic chemotherapy out of concern for developing MDS. The aim of this study was to determine if isolated del(20q) in non-myeloid disorders implies an impending myeloid disease and if treatment should be altered for such patients. Methods: We conducted a retrospective, single institution cohort study among patients who between January 2005 and July 2012 were found to have 20q deletions without other chromosomal alterations per conventional cytogenetics and non-myeloid disorders per clinical history or bone marrow biopsies. Patients with isolated 20q deletion were identified from the clinical cytogenetic laboratory database and results were reviewed per cytogeneticist for accuracy. Pathology reviewed initial and subsequent bone marrow biopsies for histopathologic or immunophenotypic evidence of a myeloid disease. If a subsequent bone marrow exam was not available, the patient's complete blood counts were reviewed to determine if they developed clinical evidence of a myeloid disorder. We defined clinical suspicion for MDS as the development of transfusion dependence (≥1 unit red blood cell transfusion every 8 weeks over 4 months), any grade = 2 anemia with either grade = 2 thrombocytopenia or grade = 2 neutropenia not related to chemotherapy or immunotherapy, or any grade = 3 cytopenia without known etiology. For patients undergoing chemotherapy, MDS was suspected if there was evidence of poor bone marrow reserve as manifest by dose modifications or delays for hematologic toxicity. Results: Thirty nine patients with isolated del(20q) were identified in the cytogenetic database from January 2005 to July 2012. Twelve out of thirty nine (31%) patients were found to have non-myeloid disorders. Three patients with multiple myeloma (25%), two patients with chronic lymphocytic leukemia (17%), two patients with autoimmune disorders (17%) and five others with breast cancer, diffuse large B cell lymphoma, monoclonal gammopathy of undetermined significance, Crohn's disease and melanoma. There were an equal number of men and woman with median age of 60 years (range 30–83 years) at the time of isolated del(20q) detection. Six patients were found to have del(20q) at the initial presentation of their disease and six developed del(20q) after undergoing treatment. Nine patients were treated with standard first line systemic therapies. Six of the nine patients were treated with chemotherapy and four of them did not have to undergo any dose modifications due to myelosuppression. In the patients with chronic lymphocytic leukemia, FCR (Fludarabine,Cyclophosphamide and Rituximab) was dose modified and later discontinued due to persistent neutropenia and thrombocytopenia. After a median follow up of twenty two months (range 2 – 64 months) no patients developed evidence of a myeloid disorder by bone marrow pathology or clinical evidence. Conclusion: Isolated deletion of the long arm of chromosome 20 in patients with non-myeloid disorders does not result in bone marrow failure or myeloid disease, therefore physicians should not alter their treatment plans. Further patient follow up is necessary to provide more insight on the prognosis and treatment of non-myeloid disorders with isolated chromosome 20q deletion. Disclosures: No relevant conflicts of interest to declare.

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