bluuebunny/crossref_metadata_2025 huggingface dataset:
Autologous Hematopoietic Stem Cell Transplantation without Total Body Irradiation for Diffuse Scleroderma. Rapid Improvement of Skin Score.
Authors: Oyama Yu , Burt Richard K. , Traynor Ann E. , Statkute Laisvyde , Barr Walter G.
Published: April 2020

Background & Aims

Scleroderma is an immune mediated vasculopathy of unknown etiology. There is no known therapy that could alter the natural course of the disease. Patients with diffuse cutaneous disease or visceral involvement has an overall 10-year survival of 35 to 68%. Hematopoietic stem cell transplantation (HSCT) has been performed in the US, but with substantial toxicity, may be due to regimens that utilize total body irradiation (TBI). We performed autologous HSCT without TBI.

Methods

We conducted a phase I HSCT study in 5 patients with diffuse scleroderma with poor clinical features. Candidates were less than 65 years old with modified Rodnan skin score (mRSS) of more than 14 or lung diffusion capacity (DLCO) less than 80%, interstitial lung disease, elevated ESR, renal involvement, or abnormal electrocardiogram. Patients with irreversible end-stage organ involvement were excluded. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor. The graft was not manipulated. The conditioning regimen consisted of 200mg/kg cyclophosphamide (CY), and 7.5mg/kg rabbit antithymocyte globulin (ATG).

Results

The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and fluid overload that were easy to manage and without mortality. The median days for neutrophil and platelet engraftment were 8 (range 7–9) and 8 (range 0–10), respectively. The median infused CD34+ and CD3+ cell counts were 9.27 x 106/kg (range 2.35–14.7) and 2.34 x 108/kg (range 1.48–6.83), respectively. Improvement of mRSS and changes of pulmonary function {DLCO, total lung capacity (TLC)}, cardiac function {left ventricular ejection fraction (LVEF), pulmonary artery pressure (PA pressure)} and renal function (creatinine) pre-HSCT, at 6 months and at 12 months post-HSCT are in table 1. After median follow-up of 19 months (range 8–20), all patients had improvement of skin score while pulmonary, cardiac and renal function remained stable.

Conclusion

Autologous HSCT with CY/ATG is safe and may be effective. Randomized studies will be needed to confirm the efficacy of this therapy.

table 1

patient skin score (mRSS) DLCO % TLC % LVEF % PA pressure mmHg Creatinine mg/dl 1 pre HSCT 26 48 71 60 23 0.7 6 months 13 39 73 63 normal 0.7 12 months 6 44 74 64 20 1 2 pre HSCT 31 86 114 58 33 0.7 6 months 17 62 106 60 unable to obtain 0.8 12 months 17 118 112 60 28 1 3 pre HSCT 31 57 73 70 36 0.8 6 months 18 55 64 60 35 0.7 12 months 18 48 69 65 43 0.7 4 pre HSCT 24 59 83 55 unable to obtain 0.5 6 months 8 52 79 55 26 0.5 12 months 5 45 73 50 unable to obtain 0.4 5 pre HSCT 30 48 94 55 25 0.6 6 months 8 54 80 55 normal 0.7
Extreme Regression: A Statistical Technique for Finding Good or Poor Prognostic Groups, Illustrated Using Myeloma Patient Data from Intergroup Trial S9321.
Authors: Crowley John J. , McCoy Jason , LeBlanc Michael , Barlogie Bart
Published: April 2020

Extreme Regression (LeBlanc, Moon and Kooperberg, manuscript submitted) is a statistical technique for finding patient subsets with either very good or very poor prognosis. In contrast to Cox regression, which generates predictions based on linear combinations of variables, Extreme Regression results in groups based on intersections or unions of simple statements involving single covariates (eg sb2m > 3.5 and albumin < 3.5; sb2m > 3.5 or LDH > ULN). Thus, Extreme Regression is similar in spirit to tree-based regression methods, except that the goal is not to develop a complete staging system (like the new International Staging System, ISS, for myeloma, which was derived using tress-based methods) but rather to define subsets of a given size (eg 10%) with extreme prognosis. Here prognosis may be defined in terms of any type of outcome such as response, one-year mortality, overall survival, etc. To illustrate we use survival data from the Intergroup Trial S9321, which tested high dose therapy with melphalan and TBI versus a standard dose regimen of VBMCP (both after VAD induction) for newly diagnosed patients with multiple myeloma. We used as potential predictors serum beta-2 microglobulin (sb2m), LDH, albumin and creatinine as measured at baseline. There were 682 eligible patients with complete data on these four covariates. We asked the algorithm to identify roughly 10% of the patients representing a poor prognosis group, and then another 25% representing a good prognosis group. The results are shown in Figure 1, along with the intermediate group of all other patients. The poor risk group comprised 77 patients (11% of the total) and was defined by those patients with sb2m > 9 and LDH > ULN; or patients with creatinine > 5; or patients with albumin < 2. These patients had a median survival of 19 months, a one year survival of 66%, and a five year survival of 19%. The good risk group included 181 patients (27%) defined by LDH <= 67% of ULN and creatinine <= 2 and albumin >= 3.5. This group had a median survival of 67 months, a one year survival of 96%, and a five year survival of 57%. Extreme regression appears to be a promising exploratory tool when the goal is the identification of simple, interpretable subsets of patients with extreme prognosis.

Figure Figure
Autologous Hematopoietic Stem Cell Transplantation for Type I Diabetes Mellitus.
Authors: Voltarelli Julio C. , Couri Carlos E.B. , Oliveira Maria-Carolina B. , Stracieri Ana-Beatriz P.L. , Moraes Daniela A. , Godoi Dannielle F. , Coutinho Marina A. , Malmegrim Kelen C.R. , Foss-Freitas Maria-Cristina , Foss Milton C. , Simoes Belinda P. , Squiers Elizabeth C. , Burt Richard K.
Published: April 2020

Insulin-dependent type I diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic β-islet cells mediated by inflammatory T cells. The pathogenic process evolves gradually for several years and becomes symptomatic when most Langerhans islands are destroyed. Antibodies against β-cell antigens (like anti-glutamic acid decarboxylase, GAD) are markers of the autoimmune reaction and levels of proinsulin C-peptide correlate with endogenous insulin secretion. Several immunosuppressive regimens have demonstrated clinical and laboratorial benefit in early onset IDDM, presumably sparing islets reserve, but most responses were transient and long term toxicity limited their continuous use. In view of durable remissions observed in various autoimmune diseases treated with high-dose immunosuppression and autologous hematopoietic stem cell transplantation (AHSCT), we started in December/03 a phase I/II trial of AHSCT in early-onset IDDM. Patients from 12–35 years old with <6 weeks from diagnosis have their peripheral blood stem cells mobilized with 2 g/m2 cyclophosphamide and 10 mcg/kg G-CSF, cryopreserved and reinfused (>2 million/kg) after conditioning with 200 mg/kg cyclophosphamide and 4,5 mg/kg rabbit antithymocyte globulin- ATG (Thymoglobuline, SangStat). End points of the study are insulin needs (U/kg/d), glycosilated hemoglobin levels, anti-GAD titers and C-peptide levels. Four patients have been transplanted and the insulin usage of the first three patients is shown in the Figure. The first patient received high dose of steroids to prevent ATG hypersensitivity and showed increasing needs of insulin after mobilization. The other two patients received minimal (#2) or no (#3) steroid dose during conditioning and showed decreasing needs of insulin after mobilization (Figure). Patient #2 presented bilateral pneumonia while pancytopenic, recovered after treatment with antibiotics and Amphotericin-B but did not require insulin therapy. A fourth patient has just been discharged from the BMT Unit. Immunologic studies in the three patients with longer follow-up showed a progressive shift from Th1 to Th2 cytokine profile after transplantation which could provide a mechanism for the modulation of the autoimmune process by high dose immunosuppression and autologous HSC. In conclusion, the preliminary results are encouraging but must be validated with a larger number of patients (12 planned in this phase) and a longer followup (5 years).

Figure Figure
Intratumoral Expression of MIP-1b Induces Antitumor Responses in a Pre-Established Tumor Model through Chemoattracting T Cells and NK Cells.
Authors: Yu Yizhi , Luo Xiaoling , Liu Shuxun , Xie Yuan , Cao Xuetao
Published: April 2020

Direct intratumoral introduction of therapeutic or regulatory genes is a developing technology with potential application for cancer gene therapy. Macrophage inflammatory protein-1 beta (MIP-1b) is a chemokine which can chemoattract immune cells such as T cells. In the present study, murine colorectal adenocarcinoma CT26 cells were transfected with a recombinant adenovirus (AdhMIP-1b) carrying the human MIP-1b gene. 24h post-transfection, hMIP-1b levels reached approximately 980 pg/ml in supernatants of 106 hMIP-1b-transfected CT26 cells. Moreover, the supernatants exhibited chemotactic activity for CD8+ T cells, CD4+ T cells, NK cells and immature DCs. Intratumoral injection of AdhMIP-1b significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice. Intratumoral hMIP-1b gene transfer also induced powerful tumor-specific CTL responses in vivo. The therapeutic effects of hMIP-1b gene therapy were greatly reduced following in vivo depletion of both CD4+ and CD8+ T cells, but were unaffected by depletion of single T cell subsets. Immune cell depletion experiments also revealed that NK cells played an important role in hMIP-1b-induced anti-tumor responses. These results suggest that intratumoral expression of hMIP-1b has the potential effect to induce host anti-tumor immunity and may prove to be a useful form of cancer gene therapy.
Microvessel Endothelial Cells of Hematological Malignancies Harbor Disease Specific Genetic Aberrations.
Authors: Schwarzinger Ilse , Exner Markus , Esterbauer Harald , Drach Johannes , Jaeger Ulrich , Chott Andreas , Wagner Oswald , Streubel Berthold
Published: April 2020

The growth of most tumors depends on the formation of new blood vessels. In contrast to genetically unstable tumor cells, endothelial cells of tumor vessels are believed to be normal diploid cells that do not acquire mutations. We have recently observed that microvessel endothelial cells of patients with B-cell lymphomas carry lymphoma specific aberrations (NEJM351:250–9, 2004). The aim of this study was to determine whether hematological malignancies other than B-cell lymphomas also carry disease specific genetic aberrations. Using a combined immunohistochemical and fluorescence in situ hybridization assay, we investigated the endothelial cells of 5 multiple myelomas, 6 anaplastic large cell lymphomas, 1 angioimmunoblastic T-cell lymphoma, 4 chronic myeloid leukemias, 3 acute myeloid leukemias and 1 acute lymphoblastic leukemia for cytogenetic alterations that were known to be present in the malignant hematopoietic cells. We found that microvascular endothelial cells of all investigated cases harbored the disease-specific chromosomal aberrations. The percentages of genetically aberrant endothelial cells were highest in chronic myeloid leukemia (median 63%) and multiple myeloma (median 42%) and lowest in anaplastic large cell lymphoma (median 15%). Our findings suggest that the genetic relationship between tumor cells and their endothelium is a common phenomenon of hematological malignancies and reflect a novel aspect of tumor angiogenesis.
Minimal Residual Disease in High and Very High Risk ALL (HR/VHR-ALL) at the End of Induction (EOI) in FRALLE 2000 B and T Protocols.
Authors: Cayuela Jean-Michel , Beldjord Kheira , Grardel Nathalie , Cavé Hélène , Auclerc Marie-Françoise , Auvrignon Anne , Leblanc Thierry , Perel Yves , Mechinaud Françoise , Schmitt Claudine , Gandemer Virginie , Schneider Pascale , Berger Claire , Rialland Xavier , Paillard Catherine , Lejars Odile , Michel Gerard , Leverger Guy , Macintyre Elizabeth A. , Baruchel Andre
Published: April 2020

From January 2000 to July 2006, 580 BCR-ABL negative patients with HR/VHR-ALL (200 T-ALL and 380 BCP-ALL (age≥10 or WBC≥50 or CNS+ or MLL-R) were included in the FRALLE 2000-BT trials. Induction regimen is prednisone (PRED) prephase + IT MTX, VCR, L-Aspa, DNR 120mg/m2 cumulated dose or DNR 160mg/m2 + cyclophosphamide 1g/m2 (T-ALL and D21 M2M3 marrow or MLL-R BCP-ALL). MRD at EOI is quantitatively determined by DNA-based PCR for Ig/TCR rearrangements either competitive PCR with GeneScan analysis or RQ-PCR with clone specific primers (sensitivity ranges 0.5×10−3–10−3, and 10−3–10−5, respectively). MRD status at EOI are available for 425 out of 552 CR (77%). MRD results are reported as negative, positive <10−3, highly positive (10−3≤MRD<10−2), very highly positive (≥10−2). Patients with EOI MRD ≥10−2 were to receive an intensified treatment.

Results:

30% (89/293) of HR/VHR BCP-ALL and 34% (45/132) T-ALL have detectable MRD at EOI, NS. A high or very high MRD is encountered in 16% (47/293) of BCP-ALL and 21% (27/132) of T-ALL (NS). Surprisingly 57% (20/35) of the pts with BCP-ALL and D8 poor PRED response (PPR) and 71% (36/51) of the pts with D8 PPR T-ALL have a negative or slightly positive MRD (<10−3) at EOI, NS. 30% (7/23) of the pts with D21 M2M3 BCP-ALL and 46% (6/13) of the pts with D21 M2M3 T-ALL have also a negative or slightly positive MRD (<10−3) at EOI. By contrast, 11% of good early responders (D8 good PRED response and D21 M1) with BCP-ALL or T-ALL (27/245 and 11/74, respectively) have a high or very high positive MRD. Overall, 20 out of 449 (4.5%) HR/VHR pts in CR have received an intensified treatment due to a very high MRD only. 3y DFS for pts with a highly positive or very highly positive MRD are 65±7% (BCP-ALL) and 64±9% (T-ALL), NS. 3y DFS for pts with a negative or slightly positive MRD (<10−3) are 94±2% (BCP-ALL) and 87±4% (T-ALL), p=.04. There is a statistically significant difference in term of DFS between pts with MRD≥10−3 and MRD < 10−3, p=.001 and p =.05 for BCP- and T-ALL, respectively.

Conclusions:

the incidence of high and very high MRD at EOI is identical in children with HR/VHR-BCP- and T-ALL. High and very high MRD levels are found in good early responders defined by morphology. Conversely, excellent molecular responses can be found in bad early responders. High or very high MRD values are associated to a comparable prognosis between BCP- and T-ALLs.
Minimal Residual Disease Detection by Four-Color Multidimensional Flow Cytometry Identifies Pediatric AML Patients at High Risk of Relapse.
Authors: Meshinchi Soheil , Alonzo Todd , Gerbing Robert B. , Pollard Jessica A. , Gamis Alan S. , Hurwitz Craig A. , Franklin Janet L. , Pardo Laura , Loken Michael
Published: April 2020

We previously demonstrated that the presence of residual leukemic blasts (MRD) in patients in morphologic remission was predictive of subsequent leukemic relapse. More recently, we developed a four-color multidimensional flow cytometric method using standardized rather than patient specific panels, distinguishing the abnormal cells based on “difference from normal”. The feasibility of utilizing this method, which does not require a diagnostic specimen and is applicable even if the phenotype of the leukemic clone changes was tested in a blinded study as part of the recently completed COG AML pilot AAML03P1 that enrolled 341 patients. 302/341 patients in the study consented to participate in the biology portion of the study. 223 (74%) had evaluable specimens at the end of induction I, 191 (87%) of which achieved a morphologic CR at the end of induction I. Of the 191 patients in CR at the end of induction I, 48 (25%) had evidence of MRD. The level of MRD ranged from 0.02% to 3% with 70% of patients having an MRD level between 0.1% to 1%. Relapse risk was assessed in those with and without MRD. Those with evidence of MRD were at significantly higher risk of subsequent relapse, with a relapse-free survival (RFS) from end of induction I of 36% for those with MRD compared to 70% for those without MRD (p < 0.001). The corresponding overall survival at 2 years from induction I was 63% and 86% for those with and without MRD (p=0.003). 181 patients who were in morphologic CR at the end of induction II had evaluable samples for MRD analysis. MRD was detected in 36/181 patients (20%) and presence of MRD was associated with a RFS from end of induction II of 34% compared to that of 70% in those without MRD (p<0.001). Corresponding overall survival at 2 years from induction II was 56% and 83% for those with and without MRD (p=0.009). We determined whether MRD positive patients who clear their disease have an improved outcome. There were 16 patients with detectable MRD at the end of course I with undetectable MRD at the end of course II. Relative risk of relapse for these patients was 40% vs. 30% for those who were MRD negative at both time points. Data from end of induction I and Induction II were combined to maximize our ability to identify those at high risk of relapse. This study demonstrates that flow cytometric based MRD can be utilized in a multi-institutional setting to accurately identify those at high risk of relapse. Multivariate analysis of the prognostic significance of MRD in the context of other prognostic factors including cytogenetics (CBF, etc.) and molecular (FLT3/ITD) prognostic factors will be presented.
Long Term Results of the AIEOP-All-95 Trial for Childhood Acute Lymphoblastic Leukemia. An Insight on the Prognostic Value of Dna Index in the Frame of BFM-Based Chemotherapy.
Authors: Arico Maurizio , Valsecchi Maria Grazia , Rizzari Carmelo , Barisone Elena , Biondi Andrea , Casale Fiorina , Locatelli Franco , Nigro Luca Lo , Luciani Matteo , Messina Chiara , Micalizzi Concetta , Parasole Rosanna , Pession Andrea , Santoro Nicola , Testi Anna Maria , Silvestri Daniela , Basso Giuseppe , Masera Giuseppe , Conter Valentino
Published: April 2020

Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) conducted the ALL-95 study for risk-directed, BFM-oriented therapy of childhood acute lymphoblastic leukemia (ALL), aimed at exploring treatment reduction in standard risk (SR) and intensification during continuation therapy in intermediate risk (IR) as randomized questions and treatment intensification in high risk (HR). The prognostic value of DNA index was explored in this setting. 1,744 patients were enrolled, 115 SR, 1,385 IR, and 244 HR risk. SR patients (DNA index ≥1.16 and <1.60, age 1–5 and WBC<20K, non-T, no high risk features), received a reduced induction therapy (no anthracyclines); IR patients were randomized to receive or not vincristine-dexamethasone (VCR-DEXA) pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by double reinduction phase. The event-free-survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE 1.3) and 83.6% (0.9); 85.0% (3.4) and 95.5% (2.0) in SR, 75.1% (1.5) and 87.5% (0.9) in IR, 51.0% (3.2) and 57.2% (3.3) in HR patients, respectively. Patients with favorable DNA index had superior EFS in both IR [83.8(2.7) versus 73.9(1.7)] and in HR [67.8(9.4) and 49.6(3.5)]. Of the 6 patients with DNA index. <0.8 only 1 remained in remission. As for treatment burden there was no difference between SR patients, receiving only 3 drugs, and others in Induction IA. Highest treatment burden was reported during consolidation in HR patients. In reinduction, first protocol II had figures similar to those reported during protocol II given to non-HR patients, while second protocol II in HR patients was associated with higher treatment burden Treatment reduction, although appealing, should be applied with great caution not to endanger outstanding cure rate achieved with over 80% of patients in Italy during the second half of the 90s having been cured. Contribution of HSCT in front-line therapy remains limited. In this study, favorable DNA index was associated with better prognosis in IR and HR patients defined by clinical criteria and treated with BFM-oriented chemotherapy. Continuous effort put in the genetic studies could provide novel insights for treatment of subsets of childhood ALL refractory to modern chemotherapy.
Preliminary Results of a Phase II Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults with Myelodysplastic Syndrome (MDS).
Authors: Steensma David P. , Baer Maria R. , Slack James L. , Buckstein Rena , Godley Lucy , Larsen Julie S. , Cullen Michael T. , Kantarjian Hagop M.
Published: April 2020

Decitabine (Dacogen®), a hypomethylating agent, is FDA-approved for treatment of patients (pts) with all FAB subtypes of MDS. The approved regimen of 15 mg/m2 intravenously (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days repeating q 6 wks demonstrated an overall improvement rate (CR+PR+HI) of 30% in MDS pts. An alternative regimen, in which decitabine is administered 20 mg/m2 IV over 1 hr once daily for 5 consecutive days repeating q 4 wks not only permits outpatient therapy, but also showed promising efficacy in a pilot study (Blood2007:109:52). This alternate regimen was evaluated in a multicenter study and preliminary results from this open-label single-arm Phase 2 study are reported. Eligible pts were ≥18 years (yrs) of age with MDS (de novo or secondary) of any FAB subtype (including chronic myelomonocytic leukemia with white count <12,000/μL) and International Prognostic Scoring System (IPSS) score ≥ 0.5 (Intermediate-1 (Int-1), Intermediate-2 (Int-2) and High-risk groups) as determined by complete blood counts, bone marrow assessment, and cytogenetics within 28 days of enrollment. Responses, the primary endpoint of the study, were assessed using International Working Group (IWG) criteria (Blood2000;96:3671), which existed at study initiation and also used in the Phase 3 trial with the FDA-approved 3-day regimen. Secondary objectives included evaluation of hematologic improvement, cytogenetic response, overall survival, time to acute myeloid leukemia progression or death, transfusion requirements, and toxicity. Ninety-nine pts enrolled: median age 72 yrs, 72% male, 89% de novo MDS, median time from diagnosis 153 days, and 29% with prior therapy for MDS. The distribution of IPSS risk groups was as follows: Low, 1%; Int-1, 53%; Int-2, 23%; and High, 23%. Pts have thus far been followed for one year after enrollment of the last pt, and the preliminary data are reported here. Investigator assessments of response, using pathology results at the individual study sites along with laboratory findings, demonstrated an overall improvement rate of 43%; central confirmation of results is ongoing. Pts received a median of 5 cycles of decitabine (range 1–17). Median survival has not been reached; a total of 62 pts continue to be followed. The most frequent adverse events were fatigue, fever, constipation, nausea, and neutropenia. Decitabine administered daily for 5 days in the outpatient setting demonstrated clinical activity with manageable toxicity profile in Int-1 to High risk MDS, suggesting that both the 3- and 5-day regimens provide meaningful clinical benefit to patients.
Preliminary Results from a Phase I Study of Revlimid® (Lenalidomide) in Combination with Vidaza® (Azacitidine) in Patients with Advanced Myelodysplastic Syndromes (MDS).
Authors: Sekeres Mikkael A. , List Alan , Cuthbertson David , Paquette Ronald , Loughran Thomas , Maciejewski Jaroslaw P.
Published: April 2020

Background: Early MDS becomes more advanced as immature myeloid cells proliferate, angiogenesis increases, genetic lesions accumulate, and tumor suppressor genes become inactivated through hypermethylation. Progression to acute myeloid leukemia (AML) may be prevented by targeting these defects through combination therapy, using an immunomodulatory, anti-angiogenic agent, lenalidomide (LEN), and a hypomethylating drug, azacitidine (AZA).

Methods: We conducted a multicenter, Phase I trial in patients (pts) with advanced MDS (IPSS score ≥1.5, or FAB or WHO classification with ≥5% myeloblasts) starting in 6/06, with results reported through 7/07. Pts were enrolled using a “3+3” design (See Table), and could not receive LEN or AZA previously. Cycles lasted 28 days, to a maximum of 7 cycles of therapy. The primary endpoint was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs, defined as Grade 3/4 non-hematologic toxicity or >50% neutrophil (ANC) or platelet (plt) drop without recovery by Day 56) of the combination. A secondary endpoint was response as defined by the Modified International Working Group.

Dose Level AZA Schedule LEN Schedule 1 75 mg/m2 SC days 1–5 5 mg PO days 1–14 2 75 mg/m2 SC days 1–5 5 mg PO days 1–21 3 75 mg/m2 SC days 1–5 10 mg PO days 1–21 4 50 mg/m2 SC days 1–5, 8–12 5 mg PO days 1–14 5 50 mg/m2 SC days 1–5, 8–12 5 mg PO days 1–21 6 50 mg/m2 SC days 1–5, 8–12 10 mg PO days 1–21

Results: Seven patients have been enrolled, 6 are evaluable for toxicity data. Median age was 64 years (range 52–70), 1 pt was female, and median follow-up is 5.5 months (range 1.5–13). All pts had RAEB-2; IPSS scores were 1.5 (4), 2.0 (2), and 3.0 (1), with IPSS cytogenetic risk categories of poor (1), intermediate (1), and good (5). No pt had a del (5q) lesion. Median time from MDS diagnosis was 3.5 wks (range 2–106). No DLTs occurred in Dose Levels 1 or 2, and MTD has not yet been reached. Grade 1/2 non-hematologic toxicities (n=6) included fatigue (4), injection site reaction (6), rash (3), pruritis (3), constipation or diarrhea (6), dizziness (1), and mucositis (1). Grade 3/4 non-hematologic toxicities included febrile neutropenia (1). Median ANC drop was 16.4% and plt drop was 10.4%. Although one patient was delayed 1 week in starting cycle 2 for neutropenia, there were no dose-reductions for toxicities. Four pts are evaluable for response: 2 had a complete response, 1 an erythroid response, and 1 progressive disease.

Conclusions: The combination of LEN and AZA is well-tolerated and early results suggest efficacy in advanced MDS. Responses and toxicity data from higher Dose Levels will be presented.
Risk Factors for Disease Progression in del(5q) MDS Patients Treated with Lenalidomide.
Authors: Giagounidis Aristoteles A. , Haase Sabine , Platzbecker Uwe , Germing Ulrich , Lohrbacher Vera , Ehninger Gerhard , Aul Carlo
Published: April 2020

Introduction: Lenalidomide is a novel immunomodulatory drug that is highly effective in patients with transfusion-dependent MDS with del(5q.31) chromosomal abnormality. In the recent MDS-003 study of lenalidomide, there was a 76% erythroid response rate, including 67% transfusion independence. Cytogenetic complexity or bone marrow blast percentage did not affect this response rate. A number of patients experienced disease progression to higher FAB subtypes or AML. We questioned whether lenalidomide might promote disease progression in del(5q) MDS and performed a retrospective analysis to identify risk profiles.

Methods: Fifty patients from three institutions were included in this analysis. They were partly treated within the Lenalidomide-MDS003-study. Patients were treated with an initial lenalidomide dose of 10 mg po daily. In case of grade >2 neutropenia, G-CSF and antibiotics were administered.

Results: The median age was 71 years; 31 patients were female and 20 were male. Disease progression to a higher FAB subtype or to AML occurred in 13 patients (29.5%). 7 of the 13 patients had RAEB at the first lenalidomide dose. In addition, 3 of these had additional chromosomal aberrations (2, trisomy 21; 1, complex karyotype). Of the remaining 6 patients, 2 had a complex karyotype at the first lenalidomide dose, 1 had an additional inv(9)(p11q12), and 1 had hypocellular bone marrow so no FAB subtype could be assigned. Only 2 of 50 patients (4.3%) with 5q-syndrome progressed to AML; both patients developed acute erythroid leukemia (FAB M6).

Conclusion: Within the del(5q) MDS subgroup, patients with an isolated del(5q) chromosomal aberration and a bone marrow blast count of <5% have the longest overall survival. Patients with additional chromosomal abnormalities or a higher blast percentage have a much shorter overall survival and a higher risk for progressing to AML. Our data show that progression to higher MDS subtypes or AML occurs almost exclusively in patients with additional risk factors such as >5% bone marrow blasts or additional chromosomal anomalies. Lenalidomide does not seem to increase the risk of transition of del(5q) MDS to higher stages of disease.
Therapy of Early Stage Myelodysplastic Syndrome (MDS) with Anti-Thymocyte Globulin (ATG) and Etanercept.
Authors: Scott Bart L. , Holsinger Aaron L. , Ramakrishnan Aaravind , Storer Barry , Becker Pamela S. , Petersdorf Stephen , Deeg H. Joachim
Published: April 2020

Immunosuppressive therapies have proven valuable in treating ineffective hematopoiesis in patients with Myelodysplastic Syndrome (MDS). Following an encouraging pilot trial, we evaluated the combination of equine anti-thymocyte globulin (ATGAM) and the soluble TNF receptor etanercept in a phase 2 trial. So far 23 patients with MDS (6-RA, 4-RARS, 12-RCMD, 1-RAEB-1) in IPSS risk groups low (n=8) or intermediate-1 (n=15) have been enrolled. All patients were platelet or red blood cell transfusion dependent. Nineteen patients completed therapy with I.V. ATGAM at 40mg/kg/day for four consecutive days, followed by etanercept, 25mg s.c. twice a week for 2 weeks every month for 4 months. The regimen was well tolerated and the majority of adverse events were anticipated infusional reactions related to ATGAM administration. Responses were assessed by modified International Working Group criteria. Twelve patients had hematological improvement (HI)-erythroid, 2 HI-neutrophil, and 3 HI-platelet. Five patients achieved red blood cell and one patient platelet transfusion independence. There was one complete remission in a patient with a co-existing diagnosis of multiple sclerosis. Thus, the overall response rate by intent to treat analysis among the 23 patients was 61%. Four patients did not complete their first course of therapy due to anaphylactic reaction, thrombosis of a pre-existing femoral graft, myocardial infarction, and patient preference. Among patients who completed treatment 74% had a hematological response, with duration of at least 5 months. Combination therapy with ATG and etanercept was active and safe in unselected patients with low and intermediate-1 risk MDS.
Alemtuzumab Treatment for Aplastic Anemia (AA) and Low-Risk Myelodysplastic Syndrome (MDS): Preliminary Results.
Authors: Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Seol Miee , Lee Young-Shin , Sim Soo-Kyung , Ryu Seong-Gil , Kang Young-Ah , Lee Kyoo-Hyung
Published: April 2020

We investigated the effectiveness of systemic immunosuppressive treatment using alemtuzumab (MabCampath®, Schering, Berilin, Germany) in adult patients with AA and low-risk MDS. This prospective study began on September 2005 and 11 patients, 7 severe AA and 4 MDS (RA 2, RCMD 1, RCMD-RS 1), have been enrolled onto the study. Patients received a total of 101 mg of alemtuzumab for 11 days: a test dose of 1 mg on the first day and a daily dose of 10 mg for the next 10 consecutive days. Anti-infective prophylaxis including ciprofloxacin, acyclovir, and bactrim was given for 8 weeks. One patient died of cerebral hemorrhage on 22 days after alemtuzumab treatment and another patient was lost to follow-up 123 days after the treatment. Nine patients are surviving with a median follow-up duration of 366 days. Non-hematologic toxicities were mild and transient: infusional fever/chill in 5 (grade I in all), skin rash in 2 (grade I in both), and increase of liver enzymes in 4 (grade I in all). Patients experienced transient aggravation of pancytopenia. One patient showed severe thrombocytopenia that was refractory to platelet transfusion leading to fatal cerebral hemorrhage. Lymphocyte subset analyses showed that B cells and natural killer cells recovered by 6 months, but CD4+ or CD8+ T cells remained at low levels for more than 6 months. There was no serious opportunistic infection requiring hospitalization. Three patients (27.3%) showed hematologic response to alemtuzumab treatment: partial response in 2 and complete response in one. Two partial responses occurred on 50 days (in an 18 year-old female with AA) and 157 days (in a 50 year-old male with RCMD-RS) after alemtuzumab treatment, but response duration was short in both patients (231 days and 51 days, respectively). In a 25 year-old male with RA, hematologic response occurred on 83 days after alemtuzumab treatment and complete response was attained on 237 days after the treatment. He remained in complete hematologic response on 370 days after the treatment. Our preliminary results showed that alemtuzumab treatment might be effective in some patients with AA and low-risk MDS, but hematologic response rate seemed low. This study will continue with the patients who are unresponsive to standard immunosuppressive treatment with ATG plus cyclosporine and are ineligible for allogeneic hematopoietic cell transplantation.
Gene Expression Profiles (GEP) To Predict at Least Very Good Partial Response to Velcade, Doxil, and Dexamethasone in Newly Diagnosed Patients with Multiple Myeloma.
Authors: Hari Malathi , MacDonald James , Friedman Judah , Kendall Tara , Mulligan George , Jakubowiak Andrzej
Published: April 2020

The introduction of novel agents and combination treatments in multiple myeloma (MM) has dramatically improved overall response rates and quality of responses including rates of complete and near complete response (CR/nCR) and very good partial response (VGPR). There is emerging evidence that achieving at least ≥90% disease reduction (≥ VGPR) at some point of treatment is associated with improved outcome and longer survival. Therefore, there is a need to identify patients who will likely achieve this level of reduction of disease and therefore who will have a higher likelihood of benefiting from the specific treatments. In the current study, we evaluated GEP of MM cells obtained from patients who were enrolled in a phase II clinical trial of the frontline therapy with a combination with bortezomib (Velcade), liposomal doxorubicin (Doxil) and dexamethasone (VDD). The primary objective of this research is to develop predictive biomarkers of response to VDD by identifying GEP of patient who achieve ≥ VGPR. Forty newly diagnosed patients were enrolled in the trial. The regimen was given for six 3-week cycles as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and dexamethasone at 40 mg on days 1–4 for the first 10 patients and for the remaining patients at 20 mg on days of Velcade and the day after. Updated results from 40/40 evaluable patients show 93% partial response rate (≥ PR) with 43% CR/nCR and 63% > VGPR (Jakubowiak et al., IMW 2007, Abstract PO-721). Bone marrow aspirates were obtained before therapy from patients who had given an optional consent for research samples. MM cells were negatively selected using RossetteSep myeloma antibody cocktail. Gene expression profiling was performed with 20 samples using Affymetrix Human Genome U133 Plus 2.0 microarray, of which 19 samples were evaluable. These samples were classified based on the modified uniform response criteria with an addition of nCR and minor response (MR) (Durie et al, Leukemia2006;20:1467) as either ≥ VGPR, (includes VGPR and CR/nCR), or <VGPR (includes PR and MR). There were 9 samples classified as ≥VGPR and 10 samples that were <VGPR. GEP analysis revealed 166 genes that were differentially expressed in patients with ≥ VGPR compared with patients with <VGPR (p < 0.001). Further analysis indicated that many of these genes may play a role in cell cycle control, signal transduction, apoptosis, and gene transcription. We plan a comparison of GEP signatures of patients with ≥ VGPR to VDD with those identified in the APEX studies for Velcade alone. The study described here provides evidence that GEPs of samples derived from patients before treatment is a useful tool in clinical trials to prospectively evaluate MM patients for individualized therapy with the goal of minimizing toxicity and maximizing efficacy.
bcl-2 Translocation [t(14;18) (q32;q21)] Does Not Correlate with Poor Clinical Outcome in Multiple Myeloma Patients Treated with Bortezomib.
Authors: Ailawadhi Sikander , Mashtare Terry L. , Coignet Marie V. , DePaolo Dawn M. , Miller Kena C. , Padmanabhan Swaminathan , Wilding Gregory , Starostik Petr , Chanan-Khan Asher A.
Published: April 2020

Background: Overexpression of bcl-2 gene mediated by t(14;18) (q32;q21) results in increased transcription of the anti-apoptotic bcl-2 protein. This is associated with aggressive clinical behavior, resistance to conventional chemotherapy regimens and poor survival in multiple myeloma (MM) patients. Impact of novel therapeutic agents such as bortezomib has not been studied in context with this adverse molecular marker. Thus we investigated the clinical efficacy of bortezomib in MM patients who were positive for bcl-2 translocation.

Methods: All MM patients treated with bortezomib or bortezomib-based therapies were evaluable for this analysis. bcl-2 translocation was studied by a nested PCR-based assay of patient bone marrow samples. The test is reproducibly sensitive to a detection level of 1:100,000 and reported as positive or negative, indicating either the presence or absence of t(14;18). Response to treatment was classified as per EBMT criteria. To study the statistical relationship between pairs of nominal variables, Fisher’s exact test was used. To study the statistical relationship between nominal and ordinal variables, exact Wilcoxon test was used. A 0.05 nominal significance level was used in all testing.

Results: Sixty six patients met the inclusion criteria of MM diagnosis and treatment with bortezomib-based regimens. Of these, bcl-2 analysis was available for 41 patients. Six patients (14.6%) were bcl-2 positive and 35 (85.4%) were bcl-2 negative. Median age was 61 years (range 40–80 years), with 18 (43.9%) females and 23 (56.1%) males. Twenty three patients (56.1%) had Durie-Salmon (DS) stage IIIA disease. Lytic bony lesions were present in 31 (75.6%) patients and most common Ig type was IgG kappa (43.9%). Seven patients (17%) achieved CR, 14 (34%) had PR, 16 (39%) had stable disease (SD) and 4 (10%) had progressive disease (PD). There was no significant association found between t(14;18) result and patient age (p = 0.4985), gender (p = 0.6786), DS stage (p = 0.6117), ISS stage (p = 0.5541), presence of bony lytic lesions (p = 0.1435), patients being paraprotein secretors or non-secretors (p = 1), Ig type (p = 0.0584), or response to treatment (p = 0.1066).

Conclusions: Presence of bcl-2 translocation is associated with aggressive clinical course and suboptimal response to conventional chemotherapy in myeloma patients. Although, the number of patients analyzed in this analysis is small, we did not find the presence of bcl-2 translocation to be an adverse prognostic marker in myeloma patients treated with bortezomib-based regimens.
De Novo CD5+ Diffuse Large B-Cell Lymphoma: Result of a Detail Morphologic Evaluation and Long-Term Follow Up of 128 Patients.
Authors: Yamaguchi Motoko , Nakamura Naoya , Suzuki Ritsuro , Kagami Yoshitoyo , Okamoto Masataka , Ichinohasama Ryo , Yoshino Tadashi , Suzumiya Junji , Murase Takuhei , Miura Ikuo , Hirano Masami , Morishima Yasuo , Shiku Hiroshi , Ueda Ryuzo , Nakamura Shigeo
Published: April 2020

De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is well known to have clinicopathologically and genetically different characteristics from CD5-negative (CD5−) DLBCL and mantle cell lymphoma. To obtain more clinicopathologic information of CD5+ DLBCL, we reviewed specimens from 128 cases of CD5+ DLBCL and analyzed the relationship between the morphologic features and a long-term survival. The current series includes the 109 CD5+ DLBCL cases described in our previous study (Yamaguchi M, Blood 2002). All patients were diagnosed between 1984 and 2002 as having DLBCL according to the WHO classification. They had no past history of any other lymphoproliferative disorders and were immunohistochemically confirmed to be cyclin D1-negative. Four morphologic variants were identified: common (monomorphic) (n=97), pleomorphic (n=15), giant-cell rich (n=14) and immunoblastic (n=2). Intravascular or intrasinusoidal infiltration was seen in 41% of the cases, and bi-nucleated snowman-like cells were seen in 80% of the cases. BCL2 protein expression in CD5+ DLBCL was more frequent than that in CD5− DLBCL (P=0.0009). Immunohistochemical analysis in a serial 45 cases of CD5+ DLBCL revealed that 80% of CD5+ DLBCL cases (36/45) were classified as non-germinal center B-cell type DLBCL. CD10 was positive in 8 cases (18%), and MUM1 was positive in 93% of the cases (42/45). The estimated 5-year overall survival rate was 36% after a median observation time of 79 months. Patients with the common variant showed better prognosis than those with the other three morphologic variants (P=0.018). Multivariate analysis showed that age more than 60 at diagnosis [hazard ratio (HR) 2.25, 95% confidence interval (CI) 1.36–3.73], advanced stage (HR 1.76, 95%CI 1.06–2.93), high serum LDH level (HR 2.2, 95%CI 1.21–4.00), and histopathologic categorization (not common) (HR 1.6, 95%CI 1.00–2.59) were independent prognostic factors for survival. In all, 16 patients (13%) developed central nervous system (CNS) recurrence. Our study revealed the morphologic spectrum and a high incidence of CNS recurrence in CD5+ DLBCL, and confirmed that CD5+ DLBCL shows frequent BCL2 protein expression and it is mainly regarded as non-germinal center B-cell type of DLBCL.
Risk Factors Predisposing to Thromboembolism in Children with Cancer.
Authors: Athale Uma , Siciliano S. , Cox S. , Lathia A. , Khan A. , Pai N. , Armstrong A. , Odame I. , Chan A.K.C.
Published: April 2020

Introduction: Cancer is a major risk factor in children with TE. However, information regarding epidemiology of TE in children with cancer is scant. We conducted a retrospective cohort study to define the epidemiology of TE in children with cancer and to identify potential risk factors.

Methods: Records of children (≤18 years of age) with cancer diagnosed and treated at McMaster Children’s Hospital over past 15 years were reviewed for demographics, details of diagnosis and treatment of cancer and of TE, if any. We studied the effect of age (<10 years vs. ≥10 years), gender, type of cancer and presence or absence of intrathoracic disease (defined as mediastinal mass or any primary or metastatic pulmonary disease), type of central venous line (CVL) and CVL dysfunction (defined as persistent or recurrent difficulty of blood draw and/or infusion or documented CVL infection) on the risk of developing TE. Statistical analysis was performed using SPSS version 15.

Results: Overall 49 of 606 children (8.1%) with cancer developed TE (Table 1). Due to very low prevalence of TE in children with brain tumors, regression analyses for risk factors was performed in children with non-CNS cancers. Children with ALL (OR 4.93, 95% CI 1.60, 11.52, p=0.004), lymphoma (OR 4.18, 95% CI 1.37, 12.71, p=0.01), and sarcoma (OR 4.42, 95% CI 1.42, 13.77, p=0.01) had increased risk of TE. Older patients (age ≥ 10 years) were at higher risk of developing TE compared to younger patients (OR 2.2; 95% CI 1.2,3.96; P<0.01). Subgroup analyses showed that patients with CVL-dysfunction (33.3% vs. 9.5%; p<0.0001, 95% CI; 10.1,37.5) and those with intrathoracic disease (17.6% vs.5.7%; p=0.028, 95% CI; 2.2, 21.7) were at significantly higher risk of TE compared to those without CVL dysfunction and intrathoracic disease.

Conclusions: Overall TE is common in children with cancer. We have identified older age and type of cancer are the important risk factors predisposing to TE; children 10 years or older and those with lymphoreticular malignancy and sarcoma are at significantly higher risk of developing TE. In addition presence of mediastinal disease and CVL dysfunction increased the risk of TE. This is one of the largest comprehensive epidemiogical studies of TE in children with cancer identifying different risk factors.

Prevalence of TE according to the tyep of cancer Type of Cancer N Patients with TE % with TE (95% CI) ALL 185 26 14.5 (9.39, 19.91) Brain Tumors 131 1 0.8 (0.02, 4.20) Lymphoma 72 9 12.5 (5.88, 22.41) Sarcoma 70 10 14.3 (7.07, 24.71) AML 51 3 5.9 (1.23, 16.24) Neuroblastoma 45 1 2.2 (0.05, 11.77) Wilms’ Tumor 43 1 1.3 (0.06, 12.3) Other 9 0 - Total 606 49 8.1 (6.1, 10.5)
Corticosteroid Therapy Does Not Increase Relapse Rate after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogeneous Leukemia and Myelodysplastic Syndrome Overt Leukemia.
Authors: Imahashi Nobuhiko , Seto Aika , Watanabe Keisuke , Yanagisawa Mayumi , Nishiwaki Satoshi , Shinba Makoto , Yasuda Takahiko , Miyamura Koichi , Kodera Yoshihisa
Published: April 2020

Corticosteroid is often used after allogeneic hematopoietic stem cell transplantation (AHCT) to control graft-versus-host disease (GVHD). However, it is concerned that corticosteroid therapy may suppress graft-versus-leukemia (GVL) effect and may increase the risk of leukemia relapse after AHCT. The aim of the present study is to determine whether the corticosteroid administration increases the relapse after AHCT for acute myelogeneous leukemia (AML) and myelodysplastic syndrome overt leukemia (MDS overt leukemia). We analyzed 98 patients who received their 1st AHCT for AML (n=78; 47 1st or 2nd complete remission, 31 advanced stage) or MDS overt leukemia (n=20) from related (n=45; 37 HLA matched, 8 HLA mismatched) or unrelated (n=53; 37 HLA matched, 16 HLA mismatched) donors at our institution between 1997 - 2006. The median age was 42 years (range, 18–64). Conventional conditioning regimen was used in 71 patients and reduced-intensity conditioning regimen was used in 27 patients. GVHD prophylaxis was cyclosporine and methotrexate in 48 patients, tacrolimus and methotrexate in 49 patients, and cyclosporine alone in 1 patient. Univariate Cox regression analysis showed AML other than 1st or 2nd complete remission (CR) and HLA mismatch were the significant risk factors for relapse but corticosteroid administration (analyzed in time-dependent fashion) was not: AML other than 1st or 2nd CR (p=0.0230, hazard ratio(HR) 2.373, 95% confidence interval (CI) 1.126–4.999), HLA mismatch (p=0.0045, HR 2.776, 95% CI 1.373–5.613), and corticosteroid administration (p=0.8483, HR 1.067, 95% CI 0.551–2.065). In multivariate analysis, corticosteroid administration did not significantly increase the risk for relapse: HR was 0.760 (95% CI, 0.379–1.524, p=0.4394) after adjusting for disease status and HLA disparity. Corticosteroid is concerned to hamper GVL effect, resulting in increased relapse rate after AHCT. However, in this study, corticosteroid administration after AHCT was not a risk factor for relapse. This may be explained by the fact that among the 54 patients who had corticosteroid administration 45(88.9%) had acute and/or chronic GVHD, resulting in relatively strong GVL effect. On the other hand, there were 7 patients who had neither grade II to IV acute GVHD nor chronic GVHD but had corticosteroid administration. Among them 2 patients relapsed. In conclusion, the result of this study suggests that corticosteroid therapy does not increase relapse rate after AHCT at least in the presence of GVHD. However, larger number of patients is needed to evaluate the effect of corticosteroid therapy on relapse in the absence of GVHD.