Yishai Ofran

Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death

We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage.

Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial

BACKGROUNDnCarbapenem-resistant Enterobacteriaceae (CRE) are emerging. In attempt to eradicate CRE colonization, we conducted a semirandomized, prospective, controlled trial using oral nonabsorbable antibiotics.nnnMETHODSnConsecutive hospitalized CRE carriers were studied. Patients whose rectal isolates were gentamicin sensitive but colistin resistant were treated with gentamicin. Patients whose isolates were colistin sensitive but gentamicin resistant were treated with colistin. Patients whose isolates were sensitive to both drugs were randomized to 3 groups of oral antibiotic treatment: gentamicin, colistin, or both. Patients whose isolates were resistant to both drugs, and those who did not consent, were followed for spontaneous eradication.nnnRESULTSnOne hundred fifty-two patients were included; 102 were followed for spontaneous eradication for a median duration of 140 days (controls), and 50 received 1 of the 3 drug regimens: gentamicin, 26; colistin, 16; both drugs, 8, followed for a median duration of 33 days. Eradication rates in the 3 treatment groups were 42%, 50%, and 37.5%, respectively, each significantly higher than the 7% spontaneous eradication rate in the control group (P < .001, P < .001, and P = .004, respectively) with no difference between the regimens. No significant adverse effects were observed.nnnCONCLUSIONnOral antibiotic treatment with nonabsorbable drugs to which CRE is susceptible appears to be an effective and safe for eradication of CRE colonization and, thereby, may reduce patient-to-patient transmission and incidence of clinical infection with this difficult-to-treat organism.

Genetic profiling in acute myeloid leukaemia ─ where are we and what is its role in patient management

Genetic profiling in acute myeloid leukaemia (AML) is a moving target. Only 4 years ago, AML was re‐classified, based on karyotypic abnormalities. However, numerous important new mutations and other genetic abnormalities that were not considered in this classification have been identified. Current cytogenetic‐based classification is limited by the substantial number of intermediate‐risk patients in whom the preferred therapy is debatable. In addition, the majority of AML patients co‐express multiple mutations and cannot be easily categorized into predefined homogenous groups. The tremendous progress in mass sequencing allows parallel identification of multiple genetic aberrations in large cohorts. Thus, a new concept of genetic profiling has arisen. Genes and proteins biologically interact with each other; therefore, it should not be surprising that mutations in different genes interact. Prognosis is determined by the composition of mutations and aberrations in leukaemic stem cells. As a consequence, clinical decisions no longer rely on scant genetic data and require comprehensive genetic evaluation. Some non‐genetic parameters are also important and should be incorporated into the clinical decision algorithm. Genetic interaction‐based profiles are challenging and recent studies demonstrate an improvement in prognostic predictions with this model. Thus, genetic profiling is likely to have a major therapeutic impact, at least for intermediate‐risk cytogenetics.

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

Hypomethylating agents have become the standard therapy for patients with high‐risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA‐treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high‐risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29–92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 109/L and neutrophil count below 0.5 × 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130–134, 2013.

Higher Infection Rate After 7- Compared With 5-Day Cycle of Azacitidine in Patients With Higher-Risk Myelodysplastic Syndrome

INTRODUCTIONnAzacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied.nnnPATIENTS AND METHODSnHigher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy.nnnRESULTSnAfter the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patients age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008).nnnCONCLUSIONnReduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk.

BCR-ABL (Ph)-like acute leukemia-Pathogenesis, diagnosis and therapeutic options.

Recent comprehensive genetic studies revealed numerous genetic aberrations underlying a group of high-risk leukemias that share a specific activated kinase gene expression pattern. These ALLs were first recognized by the expression profile similar to that of Philadelphia chromosome-positive ALL and currently can be sub-classified by the main aberrantly activated kinase in the leukemic cells. We herein review the biological mechanisms and diagnostic and clinical challenges presented by these leukemias.

Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the “3 + 7” induction regimen for acute myeloid leukemia

Evaluation of early response during induction therapy for acute myeloid leukemia (AML) is used for prognostication and re‐induction strategy, yet the optimal evaluation time point is unknown. Clearance of bone marrow (BM) blasts by day 14 of therapy does not ensure remission; thus, some patients requiring re‐induction are neglected. This study aimed to examine the role of earlier BM evaluation during induction for predicting remission and overall survival. Results of BM testing on the 5th and 14th day of intensive induction were prospectively compared in 127 adult patients with AML. Re‐induction was given, based on Day 14 results, to 25 patients. Reduction of the BM blast count to <5% as early as by the fifth day of induction was more specifically associated with the achievement of remission compared to Day 14 (88.2% vs. 60%, respectively). Rapid responders have a better 3‐year overall survival (OS). Day 5 results are a stronger predictor of OS by multivariate analysis and better segregate long‐term survivors than the Day 14th BM count (66% vs. 30%, Pu2009=u20090.0001 and 48% vs. 37%, respectively, Pu2009=u20090.04). The Day 5 evaluation of BM carries significant clinical information. The benefit of prescribing re‐induction based on such early evaluation should be prospectively studied. Am. J. Hematol. 90:1159–1164, 2015.

Adult Nephrotic Syndrome after Hematopoietic Stem Cell Transplantation: Renal Pathology is the Best Predictor of Response to Therapy

Nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HSCT) is a rare phenomenon usually associated with graft-versus-host disease (GVHD). This systematic review of post-HSCT NS cases reported in the literature aimed to identify risk factors and unique features of the disease in this clinical setting. One hundred sixteen cases of post-HSCT NS published in the English literature between 1988 and 2015 were revealed and analyzed. The median onset of NS was 20.5xa0months (range, 3 to 174) post-HSCT. NS development was associated with acute or chronic GVHD in 87.2% of cases. Membranous nephropathy (MGN) was the most frequent pathology (65.5%), followed by minimal change disease (MCD) (19%). Complete remission of the NS was achieved in 63.5% of patients (59.1% of MGN cases and 81.3% of MCD cases; Pxa0=xa0.15). Patients presenting with MCD recovered at a median of 1.75xa0months (range, 1 to 12) and with MGN a median of 7xa0months (range, 1 to 53) (Pxa0=xa0.001). NS was treated with corticosteroids alone in 16.8% of patients and with a combination of corticosteroids and other immunosuppressive agents in 73.5% of patients. Univariate analysis failed to identify a single predictive factor of response to therapy. In conclusion, post-HSCT NS usually develops concomitant to GVHD and is associated with high rates of response to therapy. Although most patients were treated with a combination of immunosuppressive drugs, single-agent therapy with steroids may be sufficient in some cases.

Concealed dagger in FLT3/ITD+ AML.

In this issue of Blood, Ostronoff et al report a low remission rate in acute myeloid leukemia (AML) patients coexpressing FLT3/ITD and cryptic translocation t(5;11)(q35;p15.5), known as NUP98/NSD1.

Azacitidine-lenalidomide (ViLen) combination yields a high response rate in higher risk myelodysplastic syndromes (MDS)—ViLen-01 protocol

Azacitidine treatment is effective in higher risk MDS (HR-MDS), with less than 50xa0% response, lasting 2xa0years. Aza and lenalidomide (Len) have a potential synergistic effect. ViLen-01 phase IIa trial includes 6-month induction (Aza 75xa0mg/m2/day, days 1–5, Len 10xa0mg/day, days 6–21, every 28xa0days), 6-month consolidation (Aza 75xa0mg/m2/day, days 1–5, every 28xa0days), and 12-month maintenance (Len 10xa0mg/day, days 1–21, every 28xa0days). Response was evaluated according to IWG criteria. Totally, 25 patients enrolled, with an average of 76.3xa0years old (60–87), and 88xa0% with major comorbidities. Thirteen patients completed induction, 7xa0proceeded for consolidation, and 2 for maintenance. The overall response rate (ORR) was 72xa0% (18/25), with 6 (24xa0%) for CR, 3 (12xa0%) for marrow CR, and 9 (36xa0%) for hematologic improvement (HI). The 7 non-responding patients were on the study 3xa0days to 4.1xa0months. At 6xa0months, 4 of 6 evaluable patients achieved complete cytogenetic response and 2 with del (5q) at diagnosis. Adverse events (AEs) were as expected in these patients: grades III–IV, mainly hematologic—thrombocytopenia (20 patients) and neutropenia (13 patients). The common non-hematologic AEs were infections (14 patients), nausea (7), vomiting (7), diarrhea (7), and skin reactions (5). The median progression-free survival (PFS) was 12u2009±u20091.36xa0months, with median overall survival (OS) of 12u2009±u20091.7xa0months. Quality of life (FACT questionnaire) data were available for 12 patients with a tendency towards improved QoL. This trial with elderly HR-MDS patients with an expected poor prognosis demonstrates a high (72xa0%) response rate and a reasonable expected safety profile but a relatively short PFS and OS.