Low Bone Marrow Cellularity Research Articles

Abstract A037: Investigating the role of the somatic DDX41 variant in the context of DDX41 hereditary myeloid malignancy syndromes (HMMS)

Abstract Heterozygous germline variants in DDX41 are identified in ~5% of patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Recognition of the hereditary nature of such cancers and a better understanding of the factors that affect progression to malignancy has deep implications for health surveillance of patients and relatives that share a pathogenic DNA variant. DDX41 has a role in ribosome biogenesis and in opposing R-loop accumulation at promoters, but the mechanisms through which DDX41 loss drives cancer development are poorly understood. In a collaboration between Cambridge, UK and Mayo Clinic, USA we identified 85 patients with germline DDX41 variants [73/85 with germline pathogenic variants (GPV) and 12 with variants of uncertain significance (VUS)]. The majority were identified through targeted myeloid NGS upon presentation with AML (30/85) or MDS (44/85). Average age at diagnosis was 65 (35-93) with male predominance (57/85). The most common GPV was the NM_016222.4(DDX41):c.415_418dup; p.D140Gfs*2 (15/85). The majority (53.4% 39/73), also acquired a somatic variants in the other DDX41 allele (referred to as GPV+Som). The most common somatic variant (82% 32/39) was the R525H, a variant predicted to reduce the ATPase function of the helicase domain. We hypothesise that the markedly reduced DDX41 activity in cells with biallelic variants, is a key cause of progression to overt malignancy. In our cohort, we observed that somatic variants occurred at a similar frequency in association with start loss, truncating, splice, in-frame deletion, and missense GPV. However, whereas MDS was the predominant diagnosis within GPV (67.6% 23/34, AML 26.4% 9/34), AML was the most frequent diagnosis within GPV+Som (AML 51%.2 20/39, MDS 38.4% 15/39). Overall, there was a significantly higher likelihood of AML in the presence of a somatic variant (p<0.05), suggesting that there might be a dosage effect on the phenotype. This pattern was observed across all the GPV, with the exception of missense, suggesting that many might be benign polymorphysms. In addition, although somatic variants are typically subclonal (overall mean variant allele fraction VAF=9.87%, 3-27.8%), we observed a higher somatic VAF in AML over MDS cases (12.4% vs 7.7% respectively p<0.05). A lower bone marrow cellularity was also characteristic of GPV+Som vs GPV alone (mean observed/expected cellularity for age 0.9 vs 1.32 respectively p<0.05). In two cases, serial bone marrow morphology and NGS data were available, and we observed marked reduction in bone marrow cellularity upon acquisition of the R525H clone. The mechanisms of AML evolution appear different in DDX41 HMMS compared to sporadic cases. Interestingly, over half of our patients (21/34 GPV and 23/39 GPV+Som) did not exhibit additional somatic drivers. Our work suggests that acquisition of a somatic variant is a critical event in disease progression. Furthermore, the near universally subclonal nature of somatic variants suggest that they may affect disease phenotype through non-cell autonomous mechanisms. Citation Format: Ludovica Marando, Talha Badar, Yael Kusne, Audrey Morris, Terra Lasho, Abhishek Mangaonkar, Christy Finke, Carles Crawley, James M. Foran, Aref Al-Kali, Andrew King, Hassan Alkhateeb, Naseema Gangat, Chi Wong, Rong He, David Viswanatha, Faisal Basheer, Mark Litzow, Alejandro Ferrer, George Vassiliou, Mrinal Patnaik. Investigating the role of the somatic DDX41 variant in the context of DDX41 hereditary myeloid malignancy syndromes (HMMS) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A037.

Late Hematologic Recovery after CPX-351 Induction Chemotherapy in AML: Predictive Disease and Patient's Factors and Their Impact on Survival

In a randomized Phase III trial, CPX-351has shown to be more effective than conventional 3+7 chemotherapy as frontline treatment for secondary or therapy-related AML. However, longer time for haematologic recovery (HR) after induction cycle (IC) was observed among CPX-351 treated patients. Later real-world evidences confirmed this observation, noting in addition that the time to HR was quite variable among different patients, as some patients showed quick recovery whereas others showed very delayed HR. However, despite the high clinical relevance, no specific factors related to a longer time to HR have been identified in CPX-351 treated patients so far.The aim of this study was to identify patients-related factors related to delayed HR and the outcome of patients showing a late HR. Data from 130patientswith newly diagnosed AML who received 1 or 2 cycles of CPX-351 were retrospectively collected. All patients received the EMA-approved dosing and schedule of CPX-351. Median age was 66 years (32-78). MDS-related cytogenetic abnormalities(CA) were found in 68 patients (52%), whereas MDS-related genetic abnormalities in absence of CA were found in 30 patients (23%). 32 patients had t-AML (24%) and 61 (47%) had a previous diagnosis of MDS. The CR+CRi rate after induction cycle was 67%. 89/130 pts received a second course of CPX-351 after IC, with CR+CRi rate of 71% after the second induction course. Among 92 pts who achieved CR/Cri, 88 were evaluable for flow cytometry-based MRD and among them 62 (71%) had reached negativity. Forty-two patients underwent allogeneic stem cell transplantation (ASCT) in first CR (32%, 46% of responding patients), with a median time to transplant of 213 days (range 52-638). Nine more patients received ASCT in second CR. After a median follow-up of 23 months (IC 95% 14.4 - 36.7), the median OS was 21 months (95% CI 17.5-25.7). In responding patients, median time to neutrophils (PMN) >0.5×109/L and platelet (PLT)>20×109/L recovery was 32 (14-54) and 31 (10-94) days, respectively. Seven patients never achieved PMN or PLT recovery even if in CRi. A total of 23 patients (18%) showed a late HR, defined as a time to PMN >500 recovery > 35 days and/or PLT>20.000 > 40 days). Only a low bone marrow cellularity at diagnosis correlated with late HR (p<0.05), whereas no correlation between late HR and baseline patient's characteristics (sex, age), disease characteristics at diagnosis (cytogenetic risk, AML subtypes, diagnostic qualifiers, molecular profiles) or adverse events (bleeding, FUO, sepsis) was disclosed. Most patients with late HR showed no CA (68%), 26% of patients showed int risk CA, and only two patients (9%) had high risk CA. Interestingly, patients with late HR showed very high MRD negativity rate (19/22, 86%) and, while time to allo-HSCT was significantly longer, OS was not different from what observed in patients achieving CR without late HR. In conclusions, CPX-treated patients who show a late HR are likely to be affected by AML progressing form MDS with low cellularity, having less adverse cytogenetic risk (hypoplastic/aplastic MDS). Those patients, despite the long time to HR, usually show a good response to CPX and an outcome superimposable with responding patients with normal time to HR time.

Clinical implications and genetic features of clonal cytopenia of undetermined significance compared to lower-risk myelodysplastic syndrome.

Clonal cytopenia of undetermined significance (CCUS) is characterized by persistent cytopenias with genetic aberrations, which do not meet the diagnostic criteria for myelodysplastic syndrome (MDS). We aimed to compare the clinical and genetic characteristics of CCUS with lower-risk MDS and identify patients with CCUS with a high risk of progression. We performed targeted sequencing of bone marrow (BM) samples from patients with idiopathic cytopenia of undetermined significance (ICUS) (n=139) and MDS (n=226). Overall survival (OS) of patients with CCUS (n=78) was worse than non-clonal ICUS (n=61) and superior to lower-risk MDS (n=99). Patients with CCUS showed similar characteristics to those with lower-risk MDS, except for higher haemoglobin, lower BM cellularity, and less frequent SF3B1 mutations. Lower haemoglobin, DDX41 (biallelic germline and somatic), ETV6, and RUNX1 mutations were independent prognostic factors for worse OS. Lower haemoglobin and DDX41 mutations were also associated with lower progression-free survival. Patients with CCUS with high-risk features showed similar or worse OS than patients with lower-risk MDS. Our findings suggest that patients with CCUS having certain clinical or genetic features should be regarded and treated as lower-risk MDS despite lacking significant dysplasia or MDS-associated chromosomal abnormalities.

Impact of Immunophenotype and Cytogenetics in Early Assessment of Post Induction Response in Acute Myeloid Leukemia (AML)

OBJECTIVE: The goal of this study was to determine whether flow cytometry and genetic estimation of blast populations in bone marrow samples from adult patients undergoing induction chemotherapy for AML were consistent with morphologic evaluation.BACKGROUND: Early post induction evaluation is paramount to assess the need for additional treatment in patients with AML. Yet, low bone marrow cellularity lends uncertainty to evaluation on the level of residual disease. This study evaluates whether standard addition of multi-color flow cytometry and karyotype analysis by fluorescent in situ hybridization (FISH) examination can assist in determining residual disease and guide further therapyMETHODS: Fifty newly diagnosed adult patients with AML who received seven days of continuous infusion cytarabine and three days of anthracycline ('7+3') at a single institution between February, 2013 and March, 2015 were identified for this analysis. Patients were divided into three groups according to day-14 bone marrow biopsy evaluation: 1) those with ² 5% blasts; 2) those with ³ 5% blasts, and bone marrow cellularity > 20%; and 3) those with ³ 5% blasts, and bone marrow cellularity ² 20%. Results were considered concordant if the parameters being compared were both <5% or >5%.Table 1Patient CharacteristicsNumber of Patientsn = 50Median Age58.5 years (range 19-73 years)Male: Female1.27:1Risk stratification by ELNLow = 10 (20%) Intermediate-1 = 4 (8%) Intermediate-2 = 14 (28%) High Risk = 17 (34%) Indeterminate = 5 (10%)Antecedent MDSn = 14, 28%Therapy-related AMLn = 2, 4%FLT-3 mutation (ITD or TKD)n = 8, 16%Overall response56% CR, 18% CRi, 26% Induction FailureRESULTS: Patient characteristics are described in Table 1. Informative results for FISH and flow cytometry were available in 56% and 86% of cases, respectively. Results from bone marrow evaluation of each subgroup are detailed in Table 2. Bone marrow interpretation based on flow cytometry versus morphologic estimation of myeloblasts was consistent in 60% (n = 26 of 43) of all mid-cycle samples. Immunophenotype demonstrated lower disease burden in the discordant cases (N=17). Among patients with chromosomal abnormalities (N=28), bone marrow myeloblast percentage based on FISH was consistent with morphologic evaluation in 60% ofsamples. FISH demonstrated higher disease burden in all discordant cases (N=11).Table 2Bone Marrow Evaluation² 5% blasts³ 5% blasts, and > 20% cellular> 5% blasts,and ² 20% cellularn, % totaln = 26, 52%n = 6, 12%n = 18, 36%Mean age53.466351.5European Leukemia Net (ELN) Risk-stratificationLow = 8 Intermediate-1 = 2 Intermediate-2 = 5 High Risk = 8 Indeterminate = 3Low = 0 Intermediate-1 = 0 Intermediate-2 = 2 High Risk = 2 Indeterminate = 2Low = 2 Intermediate-1 = 2 Intermediate-2 = 6 High Risk = 7 Indeterminate = 1Response to induction, all cyclesCR = 16/26 = 62% CRi = 6/26 = 23%CR = 2/6 = 33% CRi = 1/6 = 17%CR = 10/18 = 56% CRi = 2/18 = 11%Consistent interpretation based on morphology and flow cytometry22/23 = 96%1/5 = 20%3/15 = 20%Consistent interpretation based on morphology and cytogenetic/FISH analysis10/14 = 71%4/4 = 100%3/10 = 30%CONCLUSIONS:Our data identifies a significant proportion of patients for whom the decision to administer a 2nd cycle of 7+3 chemotherapy is unclear based on day-14 bone marrow evaluation (i.e., > 5% myeloblasts, and ² 20% cellular). Standard immunophenotyping at day 14 did not assist interpretation of chemotherapy response, possibly because of sample hemodilution. However, when available, karyotyping with FISH demonstrated a better assessment of disease burden. Although the number of samples was too small to correlate with therapy response, our data suggests that future studies to quantify the leukemic clone by genetic analysis and correlate these results with clinical outcome may improve prognostication based on mid-cycle bone marrow responsiveness to chemotherapy. DisclosuresMichaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy. Hamadani:MedImmune: Consultancy; Cellerant: Consultancy; Takeda: Research Funding; Celgene: Consultancy. Fenske:Pharmacyclics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria.

CALR, JAK2, and MPL mutation profiles in patients with four different subtypes of myeloproliferative neoplasms: primary myelofibrosis, essential thrombocythemia, polycythemia vera, and myeloproliferative neoplasm, unclassifiable.

We investigated mutation profiles of CALR, JAK2, and MPL in 199 Korean patients with myeloproliferative neoplasms (MPNs). In total, 199 patients with MPN (54 primary myelofibrosis [PMF], 79 essential thrombocythemia [ET], 58 polycythemia vera [PV], and eight MPN-unclassifiable [MPN-U]) and 4 patients with acute panmyelosis with myelofibrosis (APMF) were retrospectively subjected to Sanger sequencing for CALR, JAK2, and MPL. The overall frequency of CALR mutations was 12.6% (type 1 mutation, 16 patients; type 2 mutation, nine patients): most frequent in MPN-U (37.5%), followed by ET (17.7%) and PMF (14.8%). CALR mutations were not found in PV or APMF. CALR and JAK2 or MPL mutations were mutually exclusive. In PMF, the CALR mutations were associated with lower levels of leukocytes, lower bone marrow cellularity, and higher number of megakaryocytes. Patients with CALR-mutated ET more frequently progressed to the accelerated or blast phases compared with patients with JAK2 mutations. CALR mutations were frequently observed in the JAK2-negative MPNs, most frequently in MPN-U. The prognostic significance of CALR mutations likely differs among the MPN subtypes.

Long-Term Outcome of Lower-Risk MDS Patients after Immunosuppressive Therapy (IST) with Anti-Thymocyte Globulin (ATG)+/- Cyclosporin A (CsA)

Introduction:Long-term outcome of patients with IPSS low or int 1 (LR) MDS treated by IST with horse or rabbit (hATG or rATG) +/-CsA is not well described and patient selection criteria for such a therapy remain ill-defined in daily practice, including after resistance to erythropoiesis stimulating agents (ESA).Methods: We report the outcome of 15 consecutive LR-MDS patients treated in our institution between 2005 and 2013, with h or rATG (15 mg/kg/d for 5 days and 3.5 mg/kg/d for 5 days, respectively), +/- CsA 2 mg/kg BID for 6 months (m). The use of h or rATG formulation was based on institutional practice and availability. Patients with altered renal function or vascular contra-indication to CsA (mostly due to age) only received ATG. Bone marrow (BM) blasts were counted over 500 cells in cases of very low BM cellularity and over 1,000 cells otherwise. FISH analysis of chromosomes 5 and 7 was performed in case of cytogenetic failure. IST response probability score (ISTRPS) was calculated according to Saunthararajah, Blood 2003. Overall response rate (ORR), including complete response (CR), assessed at 12 m, and progressive disease (PD) were defined according to IWG 2006 criteria. Transfusion independence (TI) was defined as independence from RBC transfusion for at least 8 weeks.Results: Median age was 60 years (y) (range 46-77). Median follow-up was 8.1 y. All patients were RBC-transfusion dependent (RCTD). Median RCTD duration was 4.9 m (0-42). Platelet counts were <50 109/L and <20 109/L in 85% and 50% of patients, respectively. Median ANC was 0.95 109/L (0.18-4.5). WHO classification was RA, RCMD, RAEB-1 and non assessable due to very low BM cellularity in 5, 6, 2 and 2 patients. Median BM blast percentage was 1% (0-8). BM cellularity was reduced in 9/14 (64%) evaluable patients. Cytogenetics according to IPSS-R was very good, good and intermediate, in 2 (13%), 10 (67%) and 1 (7%) respectively and failed in 2 (13%). IPSS-R, assessable in 14 patients, was low, int and poor in 7, 6, 1. 7/14 patients had a DRB15 allele. ISTRPS was high in 4/15 patients. A PNH clone was detected by flow in 4 patients. A large granular lymphocyte population, a TCR clonal rearrangement and clinical or serological features of an associated immune disorder were present in 7/11 (63%), 4/10 (40%) and 5/14 (36%) patients, respectively. 6/14 patients had received at least one prior therapy for MDS including ESA in 5 and CsA, androgens, steroids, thalidomide, lenalidomide in 2, 3, 3, 1, 1 patients, respectively. 10 patients received hATG (66%), 5 (34%) rATG, combined to CsA in 7/15 (46%). In the 14 patients evaluable for response (early death, n=1), ORR including TI was 7/14 (50%) (4 CR and 3 HI; 6 TI). Median time to TI was 5.5 m (1-8). Median TI duration was 6.2 y. The only significant prognostic factors of TI were BM blast counts (60% if BM blasts ≤2% versus 0 if BM blasts >2%, P=0.04) and RCTD duration (62.5% if RCTD ≤6 m versus 0 if RTCD >6 m, P=0.02). There was a trend for a higher TI rate with lower platelet counts (P=0.13) and high ISTRPS (P=0.14). By contrast age, using a 60y cut-off, and presence of a DRB15 allele were not predictive of TI (P=0.58 and 0.31) in this cohort. Two relapsed patients were retreated with hATG +CsA and achieved a second durable response (1 CR (45m+) and 1 TI (9m+)). One non-responding patient, who subsequently developed full-blown PNH, responded to CsA and eculizumab. 5-y cumulative incidence of PD and AML were 42% and 6% respectively and median OS was 5.6 y. Median OS was not reached in responders versus 22 m in non-responders (P=0.004 by log-rank test). A single toxic death from a hemorrhagic stroke occurred very early in a patient heavily pretreated for MDS-associated vasculitis. PNH clone expansion and cytogenetic evolution occurred in 2 (both responders) and 3 patients (2 responders).Conclusion: Lower-risk MDS patients responding to IST have a good long-term outcome. After relapse, durable responses to a second course of IST can be achieved. In addition to RCTD ≤6 m, BM blasts ≤2% emerged as an IPSS-R component strongly predicting response to IST. Age >60 y was not associated with worse response. Therefore, IST should be considered as a treatment option for selected lower-risk MDS patients with very low blast counts, irrespective of age. DisclosuresOff Label Use: ATG and cyclosporin A are not approved for the treatment of MDS..

Hypocellularity and insufficient expression of angiogenic factors in implanted autologous bone marrow in patients with chronic critical limb ischemia

The aim of this study was to identify the clinical parameters of absolutely poor-prognosis patients with chronic critical limb ischemia (AP-CLI). Sixteen no-option CLI patients with arteriosclerosis obliterans: ASO (nine) and non-ASO patients (seven) treated with bone marrow-mononuclear cell implantation (BMI) were analyzed. There were three AP-CLI patients (all ASO). The mRNA expression of several angiogenic factors in the implanted cells was analyzed in comparison with normal donor bone marrow. To observe the response of bone marrow components to hypoxia, normal bone marrow cells were cultured for 24 h in 2.5% O(2), and mRNA expression of angiogenic factors were measured. AP-CLI patients exhibited extraordinary low bone marrow cellularity as well as the percentage of CD34-positive cells. Among angiogenic factors, only VEGF expression was maintained in response to HIF-1, while other factors such as HGF, Ang-1, PLGF, and SDF-1 decreased in the implanted bone marrow cells of the patients with CLI compared to normal bone marrow cells. HIF-1 and all of the five angiogenic factors increased in vitro in response to hypoxia. Thus it is highly likely that angiogenic factors except VEGF do not respond to chronic ischemia in bone marrow in vivo. An organ-protection system against tissue ischemia may be applied for acute hypoxia, but it may be insufficient for chronic ischemia.

Final Results of a Phase II Study of Sequential R-CHOP and Yttrium-90 Ibritumomab Tiuxetan (RIT) for Elderly High Risk Patients with Untreated Diffuse Large B-Cell Lymphoma (DLBCL).

AbstractAbstract 1793 Introduction:Elderly patients (pts) with high risk DLBCL are one of the fastest growing demographics of pts, but advances over RCHOP21 have not been realized. These pts are often under-represented in clinical trial secondary to comorbidity, ageism, and eligibility requirements. By the age adjusted international prognostic index (aaIPI), pts >60 years (yrs) with high-intermediate (HI) and high (H) risk disease had 5 yr survival (OS) rates of 37% and 21%. Even in the RCHOP era, high risk elderly patients have event-free-survival of roughly 50%. We report the mature data from a phase II study investigating sequential RCHOP followed by yttrium-90 ibritumomab tiuxetan radioimmunotherapy (RIT) in an effort to improve these results. Methods:Untreated ASCT-ineligible pts >60 yrs, with aaIPI HI and H risk DLBCL were eligible for study. Pts received RCHOP21 × 6 cycles at standard doses with prophylactic GCSF and darbepoetin alfa. Pts with responding (CR/PR) or stable disease post RCHOP received RIT, given 6–9 weeks post chemotherapy at 0.4 mCi/kg for platelets (plt) ≥150K and 0.3 mCi/kg for plt 100–149K. Weekly CBCs were performed for 12–13 weeks or until count resolution. Rituximab levels were assessed pre-RIT in a subset of pts. Primary end-points were PFS and OS, with intent-to-treat (ITT) analysis performed for all patients. Statistics anticipated 2/3 of pts (n=43) receiving RIT, with power to demonstrate a 20% improvement in PFS/OS at 2 yrs. Results:65 pts were consented, with 2 pts having progression prior to a single cycle on protocol, leaving 63 evaluable pts. The median age was 75 (62-86), median KPS 70% (50-100%), Stage III/IV 23/74%, LDH>ULN 91%, ENS>1=45%, BM positive=11%; aaIPI HI/H 45%/55%. Moderate or greater comorbidity was present in 86% of pts (n=65) by NIA/NCI scale. 86% of pts completed RCHOP, with overall response rate (ORR) of 83% (CR/Cru 75%, PR 8%) (Cheson 1999).Fifty pts by ITT were eligible for RIT following RCHOP chemotherapy, with 44 pts ultimately treated. Reasons for discrepancy included low bone marrow cellularity (2pt), AFIB/CHF post day 0 (1 pt), abnormal baseline FISH/cytogenetics (2 pts), withdrawal of consent (1pt). Rituximab levels in 30 pts are available pre-RIT: mean 112 mcg/ml (range 41–196) and did not correlate with outcome. The RIT dose was 0.4 mCi/kg in 38 patients and 0.3 mCi/kg in 6 patients. No patient had altered biodistribution on imaging. RIT was generally well tolerated with expected hematologic nadirs at weeks 6–7. Grade 3/4 non-heme toxicity during RIT included neutropenic fever (2), transient EF decline >20% (1), hip fracture (1), anthracycline induced cardiomyopathy (grade 5), suspected CNS bleed (grade 5). Response post RIT (n=44) was CR/CRu 86%, PR 2%. Response improvement (PR->CR or CRu->CR) occurred in 7 pts (16%).Median followup for surviving pts is 42 months, with median OS and PFS not reached (0.5-74.4). KM estimates of OS and PFS at 42 months by ITT: 64% and 62% respectively. OS and PFS at 42 months for RIT treated pts (n=44): 83.5% and 74.5%. There have been only two relapse >12 months after RIT. The aaIPI (HI vs H) predicted outcomes: OS 75% vs. 49% (p=.008), PFS 68% vs. 45% (p=.01). Conclusion:Sequential RCHOP21 × 6 cycles followed by RIT in an elderly, high comorbidity, high risk DLBCL cohort is associated with very encouraging outcomes by ITT and specifically in the RIT treated pts with long term follow-up. Therapy was well tolerated in this age group and given lack of late relapses, one may hypothesize RIT is addressing minimal residual disease typically associated with recurrence. Outcome is very favorable when compared to historical controls. A prospective Phase III study is needed to confirm these results. [Display omitted] Disclosures:Hamlin:Genentech: Honoraria, Speakers Bureau; Biogen Idec: Honoraria, Speakers Bureau; Spectrum: Consultancy, Research Funding; CTI: Consultancy, Research Funding. Off Label Use: Y-90 ibritumumab tiuxetan is not approved for use in DLBCL; it is FDA approved for NHL/indolent lymphoma. Rodriguez:CTI: Research Funding. Noy:Spectrum: Consultancy. McLaughlin:Spectrum: Consultancy. Pandit Tasker:CTI: Research Funding; Spectrum: Research Funding. Zelenetz:GSK: Consultancy; CTI: advisory board.

Pharmacologic eigenvalues: beating the rap on bone marrow failure

Patients suffering from sustained acute or chronic illness often have decreased white blood cell and platelet counts as well as anemia, and bone marrow studies routinely show only decreased numbers of blood precursor cells. While much has been recently learned about the cause of isolated anemia, the pathogenesis of true bone marrow failure (i.e., low bone marrow cellularity and low counts in multiple blood lineages) has remained elusive. In this issue of the JCI, Chen et al. present evidence that overactivation of mammalian target of rapamycin signaling in HSCs is found in two mouse models of bone marrow failure, and they show that treatment with rapamycin significantly normalizes the low blood counts.

Immunomodulation property of hexane fraction of leaves of Cinnamomum tamala Linn. in rats

The leaves of Cinnamomum tamala Linn. (CT) (Lauraceae) clinically used in Ayurveda as antidiabetic and diuretic, but no reports are available towards immunomodulating property. Its hexane fraction (CTH) was orally given to rats for 10 days and delayed type of hypersensitivity (DTH), antibody production against sheep red blood cells (SRBCs), mitotic index in bone marrow cells and concanavalin A (Con A) mediated proliferation of lymphocytes were assessed. Further on 30 days treatment, change in body weight (BW), spleen weight, thymus weight, bone marrow cellularity and hematological changes were observed. It inhibited significantly the DTH response (IC(50) 1475 +/- 57.19 mg kg(-1) BW), antibody production, suppressed mitotic index in bone marrow cells along with the suppression of lymphocyte proliferation against Con A (IC(50) 63.33 +/- 1.95 microg mL(-1)). In all experiments, cyclophasphamide and dexamethasone had been used as reference drug for in vivo and in vitro studies, respectively. On 30 days treatment, the CTH (800 mg kg(-1) BW and above) significantly suppressed growth rate, increase of spleen and thymus weight and low bone marrow cellularity. In hematological examination, it inhibited total white blood cell and lymphocytes count and increased per cent of polymorphs. Thus, it could be suggested that the fraction possesses immunosuppressive property at doses, higher than 800 mg kg(-1) BW in rats.

Philadelphia Chromosome–Positive Acute Myeloid Leukemia

We performed a multi-institutional retrospective analysis of the morphologic features, immunophenotype, cytogenetics, and BCR-ABL transcript characterization of cases of Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML). We compared these cases with cases of documented chronic myelogenous leukemia in myeloid blast crisis (CML-MBC). Patients with Ph+ AML were less likely to have splenomegaly or peripheral basophilia and had lower bone marrow cellularity and myeloid/erythroid ratios than patients with CML-MBC. Additional specific cytogenetic abnormalities that typically occur in CML-MBC were less common in Ph+ AML. Of 7 patients with Ph+ AML treated with imatinib mesylate, 6 showed at least a partial hematologic response, but the responses were of a short duration (median, 2.5 months). The median survival of patients with Ph+ AML was 9 months, similar to that of patients with CML-MBC (7 months). Ph+ AML is a rare aggressive acute leukemia with some features distinct from CML-MBC.

Low-dose ara-C in myelodysplastic syndromes (MDS) and acute leukemia following MDS: proposal for a predictive model.

Patients with myelodysplastic syndromes (MDS) comprise an extremely heterogeneous group. There is a need for decision models both for predicting the natural course of the disease and the outcomes of different treatment alternatives. In 102 consecutive patients with MDS or acute myelogenous leukemia (AML) following MDS, pre-treatment variables were studied in relation to the response to treatment with low-dose ara-C. Thirty patients (29%) responded with either a complete remission or a significant rise in the hemoglobin level. For the remaining 71%, the treatment was ineffective and in some cases hazardous. The factors associated with a poor response to treatment could be divided into two groups: one included low platelet counts and the presence of chromosomal aberrations, both signs of progressive MDS with a short survival, and the other comprised morphological findings, indicating ineffective hemopoiesis. Patients with platelet counts > 150 x 10(9)/l had a response rate of 55%, compared to 24% in patients with subnormal platelet counts. Logistic regression identified low bone marrow cellularity, absence of ring sideroblasts and < 2 chromosomal aberrations as predictors of a favourable response in patients with platelet counts < 150 x 10(9)/l. These factors and the platelet count were combined in a predictive model which divided patients into three groups with different probabilities of response: one favourable (38% of the patients), with a response rate of > 50%; a second, intermediate group (33% of the patients), with a response rate of 24%; and a third, unfavourable group (29% of the patients) with only 3% responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Minimally differentiated acute leukemia

We have studied 35 adult patients with morphologically undifferentiated peroxidase-negative acute leukemia that failed to meet the criteria for acute lymphoblastic leukemia and compared them to patients with FAB M1–M7 seen by the same physicians. The diagnosis of minimally differentiated acute leukemia (MD-AL) was associated with a higher incidence of prior hematologic disease, lower WBC, fewer blood blasts, lower marrow cellularity and a tendency towards older age. Of all patients treated with AML since January 1983, those with MD-AL were less likely to get a complete remission than those with other subtypes (35 vs 64%, p = 0.03). Treatment failure was usually due to resistant disease. Analysis of outcome as a function of drugs used during induction therapy showed an advantage for regimens containing vincristine and prednisone. The leukemic blast cells of nine patients were immunophenotyped for myeloid, lymphoid and megakaryoblast/platelet antigens. Although there were too few for a full statistical analysis as was applied to the larger group of 35 patients with MD-AL, these patients had a lower bone marrow cellularity as compared to FAB M1–M7 and a low remission rate. Eight of these were found to have positive myeloid markers and met the criteria for FAB M0. We conclude that patients with MD-AL form a distinct group with characteristic presenting features and a low response rate. Outcome data suggest that vincristine and prednisone should be included in experimental induction programs.

A predictive model for the clinical response to low dose ara-C: a study of 102 patients with myelodysplastic syndromes or acute leukaemia.

The response to treatment with low-dose ara-C was studied in 102 consecutive patients; 79 with myelodysplastic syndrome (MDS) and 23 with acute myelogenous leukaemia (AML) following MDS. The aim was to find variables that could predict the response to treatment. All patients had clinical symptoms related to cytopenia. Peripheral blood values, bone marrow morphology histology and chromosomes were analysed before the start of treatment. The median survival of the patients was 9 months and a poor survival was predicted by advanced age, low platelet counts, the presence of pseudo-Pelger morphology and > or = 2 chromosomal aberrations. Thirty patients (29%) responded with either a complete remission or a significant increase in haemoglobin level. For the remaining 71%, the treatment was ineffective and in some cases hazardous. The factors associated with a poor response to treatment could be divided into two groups: one included low platelet counts and the presence of chromosomal aberrations, both signs of progressive MDS with a short survival, and the other comprised morphological findings, indicating ineffective haemopoiesis. Patients with platelet counts > 150 x 10(9)/l had a response rate of 55% compared to 23.5% in patients with subnormal platelet counts. Logistic regression identified low bone marrow cellularity, absence of ring sideroblasts and < 2 chromosomal aberrations as predictors of a favourable response in patients with platelet counts < 150 x 10(9)/l. These factors and the platelet count were combined in a predictive model which can divide patients into three groups with different probabilities of response: a favourable group, 38.6% of the patients, with a response rate of > 50%, an intermediate group, 32.7% of the patients, with a response rate of 24%, and an unfavourable group, 28.7% of the patients, with only 3% responses. While low-dose ara-C is an effective treatment for some patients, it is ineffective and hazardous for others. We present a model that can facilitate therapeutic decision making in two-thirds of patients with MDS and MDS-AML by identifying patients who should not be treated with low-dose ara-C as well as patients with a relatively high probability of response.