bluuebunny/crossref_metadata_2025 huggingface dataset:
The Hypoxic Microenvironment in Acute Myelogenous Leukemia: Critical Role of CXCR4 in the Induction of HIF-1α.
Authors: Andreeff Michael , Dietrich Martin , Corn Paul , Konoplev Sergej , Konopleva Marina , Samudio Ismael
Published: April 2020

The bone marrow microenvironment provides functional and structural support for both normal and leukemic hematopoietic stem cells. Importantly, the marrow microenvironment is known to be hypoxic. Given the many critical functions of HIF-1α, we investigated HIF-1α levels in leukemic cell lines and primary AML blasts. Surprisingly, HIF-1α expression was non-detectable in AML cells grown in suspension cultures under normoxic (21% O2) or hypoxic (1% O2) conditions. Normoxic co-cultures with bone marrow-derived mesenchymal stromal (MSC) or MS5 cells likewise did not induce HIF-1α, but hypoxic co-culture conditions induced HIF-1α protein without changes in HIF-1α mRNA levels, suggesting post-transcriptional regulation. Functionality of HIF-1α was confirmed by concomitant increase in the levels of glucose transporter glut-1, the HIF-1α downstream target. Inhibition of stroma-leukemia cell interactions with the small molecule CXCR4 inhibitor AMD3465 (Genzyme/Anormed) at 100 nM completely abrogated the induction of HIF-1α in HL-60 and MOLM13 AML cells. While SDF-1 was unable to induced HIF-1α under normoxic conditions, it did so under both physical (1% O2) and chemical (COCl2) hypoxic conditions, in two different cell lines. Inhibition of P13K (with LY294002) or MEK/ERK signaling (with CI-1040) abrogated HIF-1α induction under hypoxic conditions. Immunohistochemical staining of bone marrow samples from primary AML confirmed the presence of HIF-1α in leukemic cells localized adjacent to bone-lining stromal elements. Results suggest that

the bone marrow microenvironment of AML is hypoxic in vivo; in leukemia cells HIF-1α induction under low oxygen tension depends on the presence of stromal cells; HIF-1α induction is dependent on SDF-1/CXCR4 and is mediated by activation of P13K and MAPK signaling.

Altogether these findings suggest that SDF-1α/CXCR4 interactions contribute to the survival of leukemic cells via specific induction of HIF-1α signaling by the bone marrow microenvironment. Disruption of these interactions via CXCR4 inhibition strategies may suppress multiple pro-survival HIF-1α targets in leukemic cells.
Gentuzumab-Ozogamicin (GO) Plus Idarubicin (I) and Cytarabine (C) as Induction Treatment for Elderly Patients with Poor-Risk Cytogenetics Acute Myeloid Leukemia (AML).
Authors: Harousseau Jean-Luc , Recher Christian F.R. , Vey Norbert , Witz Francis , Lioure Bruno B.L. , Tournilhac Olivier , Himberlin Chantal , Bouscary Didier , Ifrah Norbert N.I.
Published: April 2020

Introduction. The prognosis of AML in patients over 60 years of age remains very poor. As in younger patients karyotype is a major prognostic factor. Elderly patients with poor risk cytogenetics have a dismal outcome and complete remission (CR) rates with conventional chemotherapy are usually < 45% (and < 25% if complex abnormalities). GO has been used in combination with chemotherapy in relapsed or newly diagnosed AML, but with reduced doses in order to decrease hepatic toxicity.

Methods. In this multicentric open-label Phase II study we have evaluated the combination of I (8 mg/m2/D × D1-5) + C (100 mg/m2/D × D1-7) with GO (6 mg/m2 on D3) in AML patients aged 60–75 years with poor risk cytogenetics and fit enough to undergo cytotoxic chemotherapy. Other inclusion criteria were: CD33+ AML, PS 2, de novo or secondary AML (excluding M3 and Ph1 + AML), no cardiac, renal or hepatic dysfunction.

Results. 44 pts aged 60–74 (median 68) were treated in 13 GOELAMS centers. Karyotype results were: chromosome (chr) 5 abnormalities 22, chr 7 abnormalities 26, chr 5+7 abnormalities 14, complex abnormalities 26. In 13 cases (30%) AML was secondary (chemoinduced 9, prior myeloproliferative or myelodysplastic syndrome 4). Median duration of hospitalisation was 31 D (4–51). In CR patients median duration of neutropenia was 19 D (14–28) and median duration of thrombocytopenia was 15D (5–29). Bacterial or fungal infections were documented in 71% of cases. 7 patients had severe bleeding including 3 deaths, (2 cerebral hemorrhage, 1 intestinal bleeding). Grade 2 hepatic dysfunction was seen in 30% of patients including 3 (7%) pts with veino-occlusive disease (one death). There were 17 (38%) CR (16 CR, 1 CRp), 6 (14%) toxic deaths and 21 (48%) failures. The CR rates was 41% (7/17) for patients aged 70–75 and 37% (10/27) for patients < 70 years. While CR rate was 50% (6/12) in patients with isolated chr 5 or 7 abnormalities, it was 35% (9/26) in patients with complex abnormalities.

Conclusion. In this population of elderly but relatively fit patients with poor risk cytogenetics AML the addition of GO 6 mg/m2 to conventional chemotherapy did not appear to increase the CR rate mostly because of leukemic resistance. The incidence of aplasia-related toxicities and of hepatic complications does not encourage to use higher doses of GO.
Post-Consolidation Immunotherapy with Histamine Dihydrochloride and Interleukin-2 in AML: Long Term Follow-Up of Leukemia-Free Survival and Overall Survival.
Authors: Brune Mats L. , Rowe Jacob M. , Szer Jeff , Hogge Donna E. , Catalano John , Wallhult Elisabeth , Nilsson Bo I. , Simonsson Bengt , Spearing Ruth , Allard Stephane , Stadtmauer Edward A. , Hellstrand Kristoffer
Published: April 2020

PURPOSE. To assess the long-term outcome of AML patients (pts) in complete remission (CR) after a phase III study which compared the effect of post-consolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) on leukemia-free survival (LFS) and overall survival (OS).

PATIENTS & METHODS. A multi-national, randomized, open-label, phase III study which recruited 261 AML pts in first remission (CR1) and 59 in subsequent remission (CR>1) was conducted between June 1998 and October 2000. Pts were enrolled after after termination of consolidation therapy, stratified by country and CR status, and randomized to either treatment or no treatment (standard of care, control). Forty-one % of pts were >60 yrs (median 57), and 54% were males. Study arms were balanced for known prognostic factors. Two patient populations were studied, i.e. all pts randomized (ITT population; n=320) and pts in CR1. The treatment was self-administered at home and included ten 3-week courses of low-dose IL-2 (aldesleukin, Chiron Corp) 18 000 U/kg sc bid, plus HDC (EpiCept) 0.5 mg sc bid. Cycles 1–3 comprised 3 wks of treatment and 3 wks of rest, whereas in cycles 4–10 the rest periods were 6 wks. As reported previously (Blood2006; 108:88), the trial met the primary endpoint of prolonged leukemia-free survival (LFS) for all pts randomized (p=0.008 in favor of the treatment arm) at a median of 46 months of follow-up. The present long-term assessment of efficacy was conducted in August 2006, 30 months after the lock of the original data base.

RESULTS. Follow-up forms were retrieved from 86% (n=107; 59 HDC/IL-2 recipients, 48 no treatment,) of the 124 pts pts who were alive at original study cut-off. In the long-term analysis, median LFS in the ITT population was 11 and 8.8 months in HDC/IL-2 and no treatment groups, respectively. In the CR1 population, median LFS was 15 and 9.7 months in HDC/IL-2 and no treatment groups, respectively. The benefit of treatment both for the ITT population (p=0.017) and in CR1 pts (p=0.026) was demonstrated by log-rank testing. Kaplan-Meier (KM) estimates for LFS at 60 months revealed a trend in favor of the treatment group in the ITT population (29.6 vs 20.6%; p=0.065) and a significant difference in the CR1 population (34.4 vs 21.7%, p=0.024). The median OS of CR 1 pts were 44 months (HDC/IL-2) and 28 months (no treatment), but the difference did not attain statistical significance (log rank test: p=0.22; KM estimate at 60 months: p=0.07).

CONCLUSION. Post-consolidation immunotherapy with HDC/IL-2 results in significant long-term improvement of LFS.
Comprehensive Risk Factor Analysis in 939 Adults with Acute Myeloid Leukemia Receiving Risk Stratified Post-Remission Therapy: Results of the Prospective Randomized AML96 Trial of the German Study Initiative Leukemia (DSIL).
Authors: Ehninger Gerhard , Bornhaeuser Martin , Thiede Christian , Aulitzky Walter E. , Bodenstein Heinrich , Dorken Bernd , Einsele Hermann , Gramatzki Martin , Hanel Mathias , Helm Gisela , Ho Anthony D. , Jakob Andreas , Krumpelmann Ulrich , Leimer Lothar , Link Hartmut , Mahlmann Stefan , Neubauer Andreas , Pfluger Karl-Heinz , Sandmann Mathias , Schafer-Eckart Kerstin , Schmitz Norbert , Schuler Ulrich S. , Soucek Silke , Stuhlmann Reingard , Tischler Hans-Joachim , Wagner Thomas , Wandt Hannes , Illmer Thomas , Schaich Markus A.
Published: April 2020

In a up-front randomized study, 939 adult patients up to the age of 60 years received a double induction therapy. One course of MAV (mitoxantrone 10 mg/m2 days 4–8, cytarabine 100 mg/m2 continuous infusion days 1–8, etoposide 100 m g/m2 days 4–8) was followed by one cycle of MAMAC (cytarabine 1 g/m2, every 12h days 1–5; amsacrine 100 mg/m2 days 1–5). Patients with intermediate risk cytogenetic (IRCG) and a HLA matched sibling received an allogeneic transplantation, those with poor risk cytogenetic (PRCG) were intended to be transplanted from a sibling or unrelated donor. All AML patients without an available donor received the randomly assigned first postremission therapy (PRT) mitoxantrone combined with intermediate-dose cytarabine (I-MAC; total dose 12 g/m2) or high-dose cytarabine (H-MAC; total dose 36 g/m2). As second PRT, patients with t(8;21) received an additional cycle of chemotherapy. An autologous transplantation was scheduled for IRCG and PRCG without an allogeneic donor. The CR rate was 88% for patients with t(8;21), with IRCG 71%, and 50% with PRCG. The 5-year-survival was 21% (95% CI: 16–27%) in the PRCG, 40% (95% CI: 36–45%) in the IRCG and 74% (95% CI: 60–88%) in the t(8;21) group. No difference was observed between the I-MAC and the H-MAC group. In a multivariate analysis, a significant (p<.01 for each parameter) better overall survival was observed in patients under the age of 37 years, blast count <10% at day 15, high myeloperoxidase positivity, low CD34 expression, WBC <15*10^9/L, thrombocytes >50*10^9/L, and IRCG compared to PRCG. The relapse incidence was higher in patients without an allogeneic donor, a Flt3 mutant/wildtype ratio > 0.8 or PRCG. A risk score build out of the sum of the individual hazard ratios (SHR) was able to discriminate two groups for the IRCG with a marked difference in the 5-year-survival (low SHR: 55% [95% CI: 48–62%]; high SHR: 33% [95% CI: 28–38%]) was well as for the PRCG group (low SHR: 44% [95% CI: 32–56%]; high SHR: 13% [95% CI: 7–18%]). The risk score identified in this large patient cohort may allow individual tailoring of therapeutic interventions in future AML trials.
FLAG-IM (Fludarabine, Ara-C, G-CSF, Idarubicin, Mylotarg) Is an Effective Salvage Regimen Producing High Rates of Remission (CR+CRi) in Relapsed/Refractory AML.
Authors: Goyal Sagun D. , Uy Geoffrey L. , Augustin Kristan M. , Hladnik Lindsay , Abboud Camille N. , Cashen Amanda F. , Westervelt Peter , DiPersio John F. , Vij Ravi
Published: April 2020

Despite advances in post-remission therapy, the outcome of patients (pts) with relapsed or refractory AML remains poor. In particular, pts who relapse with an initial remission duration of < 1 year, fail a previous salvage regimen, or relapse after allogeneic transplant have dismal outcomes with CR rates ranging from 0–20%. Between April 2004 and June 2007, we treated 41 pts with a novel salvage regimen, FLAG-IM, for relapsed or refractory AML. Treatment consisted of fludarabine 25mg/m2/d on d1-5, cytarabine 2000 mg/m2/d on d1-5, idarubicin 12mg/m2/d on d1-5, and gemtuzumab ozogamicin (Mylotarg) 9 mg/m2 on d8 with G-CSF 5 mcg/kg on d1 until neutrophil recovery. CD33 expression in ≥ 30% of the blast population by flow cytometry was required for treatment. Pt population consisted of 20:21(M:F) with median age of 47 years (range 16–68), and included pts with secondary AML (n=6, 15%), intermediate risk (22, 54%) and poor risk (16, 39%) cytogenetics. Treatment indication included primary refractory disease in 7 (17%), 1st relapse, 1st salvage with initial remission duration of < 1 yr in 16 (39%), and 2nd or higher salvage regimen in 14 (34%). 17 (41%) received FLAG-IM for relapse post-allogeneic transplant. Of the 41 pts treated, 38 are evaluable for response. By IWG criteria, a CR was achieved in 12/38 (32%) and CRi in 10/38 (26%) for an overall response rate of 58%. Eight (21%) had persistent disease while 8 (21%) died with aplasia. With a median follow up of 397 days (range 23–1136), the median overall survival (OS) for the entire cohort was 147 days with 1 yr KM estimate of OS is 28.7% (95%CI, 13.4–43.9). Median event-free survival was 108 days with 1 yr KM estimate of 18.9% (95%CI, 6.1–31.6). For pts who achieved a CR or CRi, neutrophil recovery (ANC>500/mm3) occurred at a median of 28 days (range 21–50). The principal nonhematologic toxicity was grade 3-4 hepatotoxicity which occurred in 13 (32%) pts which was generally transient but fulfilled criteria for VOD in 3 (7%) pts. Of the 16 pts (39%) who underwent subsequent allogeneic transplant post FLAG-IM, median OS was 1089 days vs 94 days for no transplant, p=0.0002, with 1 yr KM estimate of 52.4% (95%CI 26.4–78.2). We conclude that FLAG-IM is an effective salvage regimen for AML with high rates of remission observed in a historically refractory patient population. The high response rates have allowed subsequent allogeneic transplantation in a significant fraction of patients resulting in long term survivors.
A Phase II Study of Bortezomib (Velcade®), Cylophosphamide (Cytoxan®), Thalidomide (Thalomid®) and Dexamethasone as First-Line Therapy for Multiple Myeloma.
Authors: Jagannath Sundar , Bensinger Bill , Vescio Robert , Camacho Elber , Wolf Jeffrey , Irwin David , Capo Gerardo , McKinley Marti , Vesole David H. , Mazumder Amitabha , Crowley John , Esseltine Dixie , Durie Brian
Published: April 2020

Background: A phase II trial evaluating the response rate with sequential administration of Bortezomib, cyclophosphamide, and dexamethasone (3 cycles) followed by Bortezomib, Thalidomide, and dexamethasone (3 cycles). The primary endpoints are overall response, achievement of ≥ very good partial response (VGPR), as well as assessment of safety and tolerability. This report provides results for 25 of 43 planned eligible pts.

Methods: Pts with newly diagnosed, untreated symptomatic myeloma were eligible. Treatment consisted of three 21-day cycles of Bortezomib 1.3mg/m2 days 1, 4, 8, and 11, Cyclophosphamide 300mg/m2 IV days 1 and 8 and dexamethasone 40mg po or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of Bortezomib 1.0 mg/m2 days 1, 4, 8, and 11; Thalidomide 100 mg po daily and dexamethasone as before. Pts received thrombosis prophylaxis with ASA cycles 4–6. Upon completion of the 6 courses, pts proceeded to stem cell harvest and/or maintenance therapy. Responses were assessed by International Response Criteria.

Results: As of August 2007, 25 pts have been enrolled: median age 60 years; 65% male; 75% Stage III (D/S); IgG 66%, IgA 16%; 17% light chain only. All pts fully evaluable for response thus far (13/13 [100%]) have achieved at least PR. Of these, 7/13 (54%) have achieved ≥VGPR (with nCR/CR in 31%). The median time to PR was 2 cycles or 42 days. Maximum response occurred by cycle 4 for 12/13 (92%)pts. Overall, both components of the sequential regimen were very well tolerated. One pt had a ruptured colonic diverticulum related to dexamethasone, but recovered well and achieved nCR on trial. There have been 24 therapy attributed toxicity events ≥Grade 2 of which 11 have required drug/schedule adjustments: 3 each for cyclophosphamide (neutropenia), dexamethasone (hyperglycemia, pneumonia, perforated viscus) and Thalidomide (neuro related) plus 2 for Bortezomib (neuropathy). No deep vein thromboses (DVT) have occurred in the study. 3 pts have already proceeded to successful stem cell harvest with transplant planned.

Conclusion: The addition of cyclophosphamide and Thalidomide to Bortezomib/dexamethasone combination has improved the depth of response with ≥VGPR (54%) and CR/nCR (31%) compared to our previous 2-drug experience which produced ≥VGPR (38%). This very well tolerated new regimen is potentially an important step forward with further results and confirmation available by December 2007.
Patients with aaIPI 2-3 Diffuse Large B-Cell Lymphoma Achieve 75% Long-Term Survival Following First-Line Rituximab-Supplemented High-Dose Sequential Chemotherapy and Autograft: Final Results of the Prospective Phase II GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) Trial.
Authors: Tarella Corrado , Zanni Manuela , Di Nicola Massimo , Patti Caterina , Castellino Claudia , Crocchiolo Roberto , Zoli Valerio , Caracciolo Daniele , Magni Michele , Boccadoro Mario , Ciceri Fabio , Corradini Paolo , Gallamini Andrea , Majolino Ignazio , Mirto Salvo , Gianni Alessandro M.
Published: April 2020

Background The outcome of Diffuse Large B Cell Lymphoma (DLB-CL) has been definitely improved by the addition of the anti-CD20 rituximab to conventional chemotherapy. However, despite the advantages offered by rituximab, results are still disappointing in patients presenting with adverse prognostic factors. For these patients, rituximab-supplemented intensive programs with autograft might represent a suitable option. Thus, a prospective multicenter study has been performed using first-line the Rituximab-supplemented high-dose sequential chemotherapy program delivered with multiple autologous peripheral blood progenitor cell (PBPC) support (R-HDS-maps regimen), in DLB-CL patients with score 2 or 3 according to the age-adjusted International Prognostic Index (aaIPI). Preliminary results have been already reported (ASH 2005; Leukemia2007, 21: 1802). Updated results after a prolonged follow-up are here presented.

Methods. R-HDS-maps includes:

3 APO courses; sequential administration of hd-cyclophosphamide (CY), hd-Ara-C, both supplemented with Rituximab, hd-etoposide/Cisplatin, with PBPC harvests following hd-CY and hd-Ara-C; hd-Mitoxantrone/L-Pam + 2 further Rituximab doses; involved-field radiotherapy.

PBPC rescue was scheduled following Ara-C, etoposide/Cisplatin and Mitoxantrone/L-Pam. Six GITIL Centers participated in the multicenter study, with patients enrolled between November 1999 and September 2004.

Results. Overall, 112 consecutive patients (74 score 2, 38 score 3) entered the study protocol. There were 5 early toxic deaths (3 sepsis, 1 pneumonia, 1 JC-virus leucoencephalopathy) + one late toxic death due to pneumonia, at 10 mos.; two more patients died for secondary myelodysplastic syndrome at 3.4 and 3.6 yrs. As reported in Figures 1–2, at a median follow-up of 59 mos., 86 patients (77%) are alive; 79 (70%) are in continuous CR, with a 5-yr event-free survival (EFS) projections of 69%; no significant differences in OS and EFS between subgroups with Germinal-Center and Activated B-cell phenotype were observed.

Conclusions. R-HDS-maps regimen:

is feasible in a multicenter setting, with a toxicity similar to that of other dose-intense/high-dose regimens; offers prolonged survival to most patients with aaIPI 2–3 DLB-CL.

Its comparative efficacy versus R-CHOP-14 is being tested in an ongoing GITIL phase III study.

Figure 1 . Overall Survival of 112 aaIPI DLB-CL Figure 1. . Overall Survival of 112 aaIPI DLB-CL Figure 2. Event-free Survival according to GC and ABC phenotype Figure 2. Event-free Survival according to GC and ABC phenotype
Clinical Outcomes of Patients with Recurrent/Refractory Hodgkin Disease Receiving Cyclosporine, Interferon-γ, and Interleukin-2 Immunotherapy To Induce Autoreactivity after Autologous Stem Cell Transplantation with BEAM: A COG Study.
Authors: Chen Allen R. , Hutchison Robert , Hess Allan , Gardner Sharon , Trippett Tanya , de Alarcon Pedro , Hogan Shirley , Mitchell Joy , Massey Vickie , Constine Louis S. , Chen Lu , Schwartz Cindy L.
Published: April 2020

The major risk for patients with recurrent or refractory Hodgkin Disease (HD) who receive standard treatment with high-dose chemotherapy and autologous hematopoietic stem cell rescue (ASCR) is relapse. However, in HD, the allogeneic graft-vs.-lymphoma effect is offset by high transplant-related mortality. The Children’s Oncology Group has completed a pilot study of immunotherapy using cyclosporine, interferon-γ, and interleukin-2 to induce autologous graft-vs.-host disease (auto GVHD) in an effort to reduce the relapse rate without excessive morbidity and mortality. From 11/2003 to 2/2005, 24 patients with biopsy-confirmed recurrent/refractory HD were enrolled at 13 COG stem cell transplant institutions. One patient was inevaluable because of errors in protocol administration. At initial diagnosis, 5 were stage IV, 8 stage III, 7 stage II, 1 stage 1, and 3 unknown; 16 had B symptoms, and 15 had bulky disease. All patients had failed intensive multi-agent chemotherapy, and most had received prior radiation therapy. High risk patterns of relapse included extranodal disease (8), B symptoms (3), and bulky disease (2). We have previously presented the tolerability of this regimen, with the expected reversible complications and 4% non-relapse mortality. Moreover, we detected circulating autoreactive lymphocytes in vitro from the majority of patients during immunotherapy. These autoreactive lymphocytes respond to the HLA class II invariant peptide (CLIP). We therefore isolated these cells from selected patients by flow cytometry after staining with CLIP-DR2 tetramers, and demonstrated high perforin expression in CD8+ effector cells early in the course of immunotherapy, and a subsequent rise of FOXP3 expression in CD4+ regulatory T cells later in the course of immunotherapy. Importantly, CLIP was strongly expressed on the surface of Hodgkin Reed-Sternberg cells, as demonstrated by monoclonal antibody LN2 immunostaining of tumor samples from 8/9 patients for whom adequate tissue was submitted. To date, only 6 relapses have been reported. Updated event-free and overall survival data will be presented. We conclude that this immunotherapy regimen is tolerable, induces autoreactivity in a majority of patients, targets a molecule expressed consistently on Hodgkin Reed-Sternberg cells, and has produced encouraging clinical outcomes. We will proceed to test the efficacy of this immunotherapy regimen by randomizing patients with chemosensitive recurrent/refractory HD to receive immunotherapy or not after BEAM and ASCR.
When May Patients Be Considered Cured after Autografting for Hodgkin Lymphoma?.
Authors: Dean Robert M. , Sweetenham John W. , Jin Tao , Brown Stacey , Pohlman Brad , Sobecks Ronald , Kalaycio Matt , Andresen Steve , Copelan Edward , Bolwell Brian J.
Published: April 2020

Patients who undergo high-dose chemotherapy with autologous stem cell transplantation (ASCT) for Hodgkin lymphoma routinely undergo surveillance for post-transplant recurrence. Follow-up schedules after ASCT are based largely upon expert opinion rather than data. To formally describe the evolution of recurrence risk over time for Hodgkin lymphoma after ASCT, we used a prospectively maintained database to retrospectively evaluate the outcomes of 245 patients who underwent ASCT for Hodgkin lymphoma at the Cleveland Clinic Foundation from 1985 through 2005. Patient characteristics: male gender in 64%; median age, 34 years (range, 18–70); median time from diagnosis to transplant, 22 months (4–327); Karnofsky score > 80 in 89%; median 2 prior regimens (1–4); prior XRT in 52%; bulky disease > 10 cm in 20%; stage III-IV in 62%; disease status of CR1/PR1 in 8%, CR2/PR2 in 69%, refractory in 11%, other in 12%; preparative regimen of BuCyVP in 65%, CBV in 26%, TBI/others in 9%. Median follow-up after ASCT for all pts was 35 months (0–223); for surviving pts, 74 months (3–223). At 5 years, estimated overall survival and relapse-free survival were 47% and 36%, respectively. Relapse occurred in 115 pts, with 5-year relapse rate estimated at 44% (Figure).

Figure Figure

Landmark analyses were conducted to estimate long-term outcomes for patients in remission at various times after ASCT, as shown in the Table:

Duration of Remission after ASCT Long-Term Likelihood of Continued Remission 1 year 63.8% 2 years 78,8% 3 years 83.0% 5 years 97.0%

These data illustrate the declining threat of relapse that faces patients who achieve remission following ASCT for Hodgkin lymphoma. Most patients who are destined to experience disease recurrence after ASCT do so within the first 2 years post-transplant. Patients who remain in remission 5 years after ASCT are at extremely low risk for subsequent relapse and can be reassured that they are likely cured. This analysis provides a factual basis to support gradually decreasing the frequency of surveillance visits and to discontinue routine monitoring for relapse at 5 years after ASCT.
High-Dose Cytoxan, Etoposide, and Cisplatin Followed by Autologous Hematopoietic Cell Transplantation for the Treatment of Hodgkin Lymphoma: A 20-Year Single-Institutional Experience.
Authors: Klumpp Thomas R. , Chasky Moshe C. , Emmons Robert V. , Martin Mary E. , Gajewski James L. , Mangan Kenneth F.
Published: April 2020

Since 1988 we have treated 66 patients with relapsed, refractory, or high-risk Hodgkin lymphoma (HD) with high-dose CEP consisting of cyclophosphamide 1,500 mg/m2/day × 4 (total dose, 6,000 mg/m2), etoposide 400 mg/m2 twice daily × 6 doses (total dose, 2,400 mg/m2), and cisplatin 50 mg/m2/day × 3 by continuous i.v. infusion (total dose 150 mg/m2) followed by infusion of autologous peripheral blood stem cells (n=49), bone marrow (n=16), or both (n=1). The patient population included 41 males and 25 females. The median age at transplant was 33 years (range, 17–64 years). Twenty-three patients (35%) had never achieved complete remission prior to transplant, 36 (55%) had previously achieved a complete remission but subsequently relapsed, and 3 (5%) were in first complete remission. Information regarding the disease status at transplant was unavailable for 4 patients (6%). Twenty-seven patients (41%) remain alive and free of any post-transplant relapse or progression as of the most recent follow-up, and an additional 10 patients (15%) manifested active disease post-transplant but are currently in remission following additional post-transplant therapy, yielding a total of 37 patients (56%) currently in CR. In addition, 5 patients (8%) remain alive with active disease, 23 patients (35%) died of progressive disease, and only 2 patients (3%) died of treatment-related causes including diffuse alveolar hemorrhage (1 patient) and hepatic veno-occlussive disease (1 patient). With a median follow-up of 4.4 years among surviving patients, the Kaplan-Meier 5-year estimates for event-free survival and overall survival are 34% and 60%, respectively, and five-year survival was superior among patients who had achieved at least one CR prior to transplant versus patients who had never been in CR prior to transplant (71% versus 43%, p = 0.03). Detailed adverse events data is available regarding all patients transplanted since September 1996: Of these, only 3 (7%) suffered grade 3 or greater pulmonary toxicity, 12 (29%) exhibited grade 3 or higher mucositis, and 10 (24%) had grade 3 or higher nausea or vomiting. The median number of days from transplant to neutrophil recovery (500 cells/uL) was 10 days, whereas the median number of days to platelet recovery (20,000 cells/uL) was 12 days. We conclude that high- dose CEP followed by autologous transplant is an active and well-tolerated treatment program in patients with relapsed or refractory HD. The low incidence of pulmonary toxicity is noteworthy given that a high percentage of patients had been exposed to bleomycin and/or thoracic XRT prior to transplant, and appears to be superior to that reported with conventional CBV-conditioned transplants in patients with HD.
Phenotypic and Functional Characterization of Mesenchymal Stromal Cells Derived from CD271+- Bone Marrow Mononuclear Cells and Mesenchymal Stromal Cells Derived through Plastic Adherence.
Authors: Kuci Selim , Puetsch Kathrin , Kuci Zyrafete , Huenecke Sabine , Kreyenberg Hermann , Amara Chandra Sekhar , Piechaczek Christoph , Koehl Ulrike , Klingebiel Thomas , Bader Peter
Published: April 2020

Mesenchymal stromal cells (MSCs) are non- hematopoietic multipotent cells which can be derived from bone marrow mononuclear cells either by plastic adherence (PA-MSCs) or by a positive selection with antibodies against cell surface antigens expressed by MSC-progenitor cells (CD271, CD73, CD146, CD105, CD166, SSEA-4 and recently GD2). In this study, we compare the phenotype, proliferation potential, differentiation potential, the cytokine expression pattern and inhibitory potential of MSC- derived by plastic adherence and MSCs derived from positively selected CD271+ bone marrow mononuclear cells (BM-MNCs). According to CFU-F assay, the enriched CD271+ BM cells possess a significantly higher frequency (2952 per 1×106 BM cells) compared to PA-MSCs (21 per 1×106 BM cells). Phenotypically, both populations expressed high levels of common MSC antigens such as CD73, CD105, CD44, CD166, CD90, HLA-Class I and were negative for CD34, CD133, and CD14. Compared to PA-MSCs, CD271+ BM cells after the isolation express high levels of the hematopoietic antigen CD45 which is down- regulated within the first passage and HLA-DR, which remains constant through many passages. These cells have a 10- to 1000-fold higher proliferation capacity compared to PA- MSCs. However, both populations differentiated in vitro along adipogenic, chondrogenic and osteogenic lineage. In MLR, both populations significantly suppressed the proliferation of PHA- stimulated allogeneic T- lymphocytes at the ratio 10: 1 (MSCs:T-cells). However, CD271+ BM- derived MSCs were more efficient in secreting IFN-γ, IL-1β, IL-2, IL-4, GM-CSF and TNF-α, whereas PA- MSCs secreted significantly more IL-6 and IL-8 than CD271+ BM- derived MSCs. Ongoing in vivo studies with immunodeficient NOD/SCID mice will show the whole potential of both population in the improvement of engraftment of mobilized peripheral blood hemaatopoietic CD133+ cells. Based on their higher frequency and proliferation capacity we suggest that CD271+ BM- cells may represent a better source than PA- MSCs in order to generate bulk quantities of MSCs for clinical applications.
Inhibition of Rhabdomyosarcoma’s Bone Marrow Metastasis through Blocking of MET Receptor Signaling.
Authors: Lesko Ewa , Miekus Katarzyna , Kijowski Jacek , Drabik Grazyna , Wilusz Miroslawa , Majka Marcin
Published: April 2020

Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma belonging to family of small blue cell tumors and it represents the largest subset of soft tissue sarcomas in this age group. RMS can be divided into two major subtypes based on chromosomal analysis - embryonal (ERMS) without translocations and alveolar (ARMS) with translocations. They differ in clinical outcome with ERMS having more favorable prognosis. However, nevertheless of subtype, if RMS is diagnosed at late stage (IV) or with metastatic disease the outcome is usually poor with only 21% of 5 years overall survival. RMS gives distant metastasis to various organs but predominantly to lung and bone marrow. Recently, MET receptor, which is highly expressed on RMS cells, has been shown to mediate RMS cells motility. Since HGF, a ligand for MET receptor, is abundantly expressed by bone marrow cells, it was also postulated that MET could be involved in bone marrow metastasis of RMS (Jankowski et al. Cancer Research 2003). In this study we have shown that blocking of MET receptor expression by RNA interference (RNAi) has strong influence on metastatic behavior of RMS cells both in vitro and in vivo. Using RNAi we created both ERMS and ARMS cell lines that lack MET receptor expression as was assessed by qRT-PCR and Western blotting. We showed in vitro that these cells possessed a reduced potential to migrate toward HGF (as study by chemotaxis, invasion and “would healing’ assays) and to secrete extracellular matrix degrading enzymes after stimulation with HGF. However, we did not see any influence of MET downregulation on mitogenic potential of RMS cells. We also found that inhibition of HGF-MET signaling blocks adhesion of RMS to stromal and endothelial cells. Most importantly, inactivation of HGF-MET axis strongly suppressed the ability of RMS cells to engraft and populate bone marrow cavities both in short and long term in vivo assays. In 24 hour seeding assay all mice injected i.v. with wild type RMS had detectable tumor cells in their bone marrow as measured by qRT-PCR and flow cytometry. At the same time mice injected with MET negative cells had bone marrow cavities free of tumor. In long term assay mice were injected s.c. with 5×106 RMS and after 30 days presence of tumor cells in bone marrow was investigated. qRT-PCR analysis revealed that 100% of mice injected with wild type cells and only 50% of mice injected with RMS negative cells had metastatic tumor in their bone marrow. In summary, we conclude that MET receptor plays a very important role in facilitating metastasis of RMS into bone marrow and that blocking of HGF-MET axis could be used in the future as a therapeutic option to inhibit spreading of RMS into this organ.
Significance of Suboptimal Response to Imatinib, as Defined by the European LeukemiaNet, in Long-Term Outcome for Patients (Pts) with Chronic Phase (CP) Chronic Myeloid Leukemia (CML).
Authors: Alvarado Yesid , Kantarjian Hagop , Faderl Stefan , Burger Jan , Borthakur Gautam , O’Brien Susan , Wierda William , Garcia-Manero Guillermo , Cortes Jorge
Published: April 2020

The European LeukemiaNet recently published recommendations for evaluating response to imatinib among pts with CML. Criteria for failure and suboptimal responses were proposed. The significance of failure is accepted and constitutes grounds for change in treatment. The prognostic implications of having a suboptimal response are less clear making treatment decisions less clear in this setting. We analyzed the outcome of 281 pts treated with imatinib as frontline therapy for CML in CP: 73 at initial dose of 400mg daily and 208 at 800mg daily. Their median age was 48 yrs (range, 15 to 84 yrs) and their median follow-up 48 months (mo) (2–79 mo). After 3 mo of therapy none of the 273 evaluable pts met definition of suboptimal response according to the European LeukemiaNet, while 3 of 273 (1%) met definition for failure. At 6 mo 10/259 (4%) evaluable had suboptimal response and 9 (3%) failure. At 12 mo 19/246 (8%) had suboptimal and 14 (6%) failure, and at 18 mo 91/224 (41%) had suboptimal and 21 (9%) had failure. The probability of having a suboptimal response at 6 and 12 mo was significantly higher for pts treated with a starting dose of 400mg than those treated at 800mg: at 6 mo [12% suboptimal at 400mg vs 1% at 800mg (p=0.002)] and at 12 mo [17% and 4%, respectively (p<0.001)]. The outcome at 24 months* by the response at specific times was as follows:

Time Response % CCyR % MMR % Transf % Event CCyR=Complete cytogenetic remission, MMR=Major molecular remission, Transf=Transformation to accelerated or blast phase, Event=loss of complete hematologic response, loss of major cytogenetic response, transformation, or death 6 mo Optimal 91 60 2 6 Suboptimal 0 0 30 50 Failure 0 0 22 67 P .001 .001 .001 .001 12 mo Optimal 94 63 2 4 Suboptimal 56 25 0 16 Failure 0 0 21 57 P .001 .001 .001 .001 18 mo Optimal 98 85 0 1 Suboptimal 93 39 2 5 Failure 15 0 19 43 P .001 .001 .001 .001
Bone Marrow Reaction in Patients with Chronic GvHD - An Immunohistochemical Analysis of Microvessels and Lymphocytes.
Authors: Hill Wolfgang , Huss Ralf , Ullmann Johanna , Ledderose Georg , Tischer Johanna , Hausmann Andreas , Kolb Hans-Jochem
Published: April 2020

Chronic GvHD (cGvHD) is associated with endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in skin biopsies as well as increase of von Willebrand factor in plasma (BC Biedermann, Lancet 2002). Moreover an increased quantity of CD45RO positive lymphocytes has been observed in bone marrow biopsies (bmb) in CML pts with acute GvHD (aGvHD) grade III and lV, who were transplanted from unrelated donors (J Thiele, Bone marrow transplantation 2001). We analysed factors of T-cell activation and microvessels in bmb of pts with cGvHD to evaluate the function of the bone marrow in cGvHD.

Methods: In an associated protocol of a prospective phase II study in 35 pts for the therapy of bone loss following HSCT with a bisphosphonate one bmb was taken prior of entry into the study and embedded in paraffin after decalcification. The interval between HSCT and time of biopsy was median 477 +/−998 days. For conventional semiquantitative evaluation of marrow and spongiosa a Giemsa staining was used. For immunological quantitative evaluation the following monoclonal antibodies were used with the APAAP method: CD34 and von Willebrand factor (VWF) for endothels of microvessels and CD45RO and CD8 for T-lymphocytes subsets. The pts were divided in 5 groups:

neither aGvHD nor cGvHD; no cGvHD but aGvHD before entry; cGvHD limited; cGvHD extensive inactive; cGvHD extensive active, needing immunosuppression.

Results: Conventionally analysed no pt had evidence of vasculitis. 1 pt of group 4 had one small immunoreactive aggregate of lymphocytes another pt of group 5 had a diffuse infiltration with lymphocytes. 32 pts had no or very small reduction of spongiosa and 3 had severe reduction of spongiosa < 15%. The significant immunological results were:

Number/mm2 1. no GVHD (n=6) 2. aGvHD before (n=4) 3. cGvHD limited (n=5) 4. cGvHD ext. inactive (n=8) 5. cGvHD ext. active (n=12) p (group No) CD34+ vessels 12,6 10,4 8,5 20,7 27,9 < 0,001 (1,2,3 vs 4,5) V. Willebrand 6,5 13,2 18,6 17,6 18,9 0,005 (1,2 vs 3,4,5) CD8+ 5,8 4,0 6,8 10,2 25,3 0,034 (1,2,3 vs 4,5)

The number of CD34 as well as the number of vWF positive microvessels increased with the grade of involvement and activity of cGvHD (11,1 vs 25,3 respectively 8,7 vs 18,1). Additionally the content of CD8 positive lymphocytes increased with the grade and activity of disease. In contrast to reported skin biopsies, bone marrow capillaries were not destroyed by cytotoxic lymphocytes with increased activity. The bone marrow seems to show a different immunological reaction in contrast to pts with cGvHD of whom the target organs are skin, liver or gut. This was not observed on conventional biopsies. Further studies will be directed to the pattern of microvessels with regard to hematopoietic function and relapse.
Pre-Engraftment Serum C-Reactive Protein (CRP) Value as a Predictor of Acute Graft-Versus-Host Disease and Non-Relapse Mortality.
Authors: Fuji Shigeo , Kim Sung-Won , Fukuda Takahiro , Mori Shin-ichiro , Yamasaki Satoshi , Morita-Hoshi Yuriko , Ohara-Waki Fusako , Heike Yuji , Tobinai Kensei , Tanosaki Ryuji , Takaue Yoichi
Published: April 2020

Background: In a mouse model, it has been shown that inflammatory cytokines play a primary role in the development of acute graft-versus-host disease (GVHD). Here, we evaluated whether the pre-engraftment CRP value, which is used as a surrogate marker of inflammation, could predict post-transplant complications including GVHD.

Methods: The medical records of 224 adult patients (median age, 47 years; range, 18–68 y), who underwent conventional (CST, n=105) or reduced-intensity (RIST, n=119) allogeneic stem cell transplantation between January 2002 and July 2006 were reviewed retrospectively. Their diagnosis included AML (n=94), ALL (n=23), NHL (n=62), MDS (n=27) and others (n=18). Stem cell sources included bone marrow (n=108), peripheral blood stem cells (n=98) and cord blood cells (n=18). Patients were categorized according to the maximum CRP value during the pre-engraftment neutropenic period: the “low CRP” group (CRP < 15 mg/dL) included 157 patients and the “high CRP” group (CRP≥15 mg/dL) included 67 patients. We assessed the occurrence of acute GVHD, non-relapse mortality (NRM) and overall survival.

Results: The incidence of documented infections during neutropenia was higher in the high CRP group (34% vs 17%, P=0.004). The CRP value was significantly lower after RIST than after CST (P=0.017) or after related than after unrelated transplantation (P<0.001). A multiple logistic regression analysis showed that male sex, unrelated donor and HLA-mismatched donor were associated with high CRP values. The high CRP group developed significantly more grade II-IV acute GVHD, grade III-IV acute GVHD and NRM as shown in Figure 1 and 2. A multivariate analysis showed that a high CRP level was associated with an increased risk of grade II-IV acute GVHD, poor OS and high NRM.

Conclusion: The present findings suggest that the CRP value may reflect the net degree of tissue damage due to the conditioning regimen, inflammation, infection and allogeneic immune reactions, all of which lead to subsequent acute GVHD and NRM. Future clinical studies to evaluate the feasibility of earlier intervention and adjustment of GVHD prophylaxis based on monitoring of the early CRP value are warranted.

Fig 1 grade II-IV acute GVHD Fig 1. grade II-IV acute GVHD Fig 2 non-relapse mortality Fig 2. non-relapse mortality
Analysis of Predictive Power of Prednisone Dose at 3 Months of Treatment on CGVHD Prognosis.
Authors: Parker Pablo M. , Nakamura Ryotaro , Pullarket Vinod , Rosenthal Joseph , Smith Eileen P. , Snyder David S. , Zain Jasmine M. , Somlo George , Brown Annette , Kim Hanjoo , Palmer Joycelynne , Cai Ji-Lian , Delioukina Maria L. , Falk Peter M. , Karanes Chatchada , Kogut Neil M. , Krishnan Amrita , Nademanee Auayporn P. , O’Donnell Margaret R. , Popplewell Leslie , Sahebi Firoozeh , Spielberger Ricardo , Stein Anthony S. , Forman Stephen J.
Published: April 2020

Current CGVHD prognostic and staging systems are still undergoing development and have identified plt count; CGVHD types progressive(P), quiescent(Q), de novo(DN); KPS, and GI involvement as significant risk factors affecting outcome. A simple reproducible staging system such as used for AGVHD to apply in clinical trials is still lacking. We evaluated whether the PSE dose required to control CGVHD at 3 months from diagnosis would have a prognostic effect on survival and in and of itself serve as a criteria for secondary intervention or investigational therapy. We hypothesized that by 3 months from start of treatment patients would be on the lowest dose dictated by medical necessity rather than by physician driven dose preference. A retrospective analysis of charts from 109 patients diagnosed with CGVHD between 6/2000 and 6/2003 was done. Data collected included age, donor type(mud/sib), plt count, CGVHD type(P/Q/DN), KPS, GI involvement. Outcome analysis included survival and cause of death. PSE dose was calculated in mg/kg at 3 months from first diagnosis of CGVHD. With a median follow up of 47.2 months(range 6.6–67.2) relapse censored survival of patients on a 3 month PSE dose of more than .3 mg/kg was 53% compared to all lower doses 86%(P.03). In a univariate analysis only PSE dose (P .05) and KPS (P <.01) were significant with plt count approaching significance (P .11). In a multivariate analysis again only PSE dose and KPS were significant (Table 1).

Table Univariate Multivariate Variable Value N # of deaths Hazard Rate Ratio (95% CI) p value Hazard Rate Ratio (95% CI) p value Prednisone at 3 month 0 20 1 Baseline 0.05 Baseline 0.1–0.14 18 2 3.0 (0.3–32.7) 3.7 (0.3–43.4) 0.33 0.15–0.29 22 3 2.9 (0.3–28.2) 3.4 (0.3–34.5) 0.32 0.3–0.59 16 7 9.8 (1.2–79.4) 9.3 (1.1–76.0) 0.04 0.6–0.99 0 0 n/a n/a n/a ≥1.0 0 0 n/a n/a n/a cGVHD class Denovo 29 5 Baseline 0.54 Progressive 23 7 1.9 (0.6–6.0) Quiescent 57 13 1.3 (0.5–3.8) Donor type Sibling 48 9 Baseline 0.40 Unrelated 61 16 1.4 (0.6–3.2) Platelet count at 3 month <100 28 9 Baseline 0.11 Baseline ≥100 81 16 0.5 (0.2–1.1) 0.7 (0.2–2.3) 0.59 KPS at 3 month <80 14 7 Baseline <0.01 Baseline ≥80 95 18 0.2 (0.1–0.5) 0.3 (0.0–1.3) 0.03 Lower GI at 3 month No 98 22 Baseline 0.78 Yes 9 2 1.2 (0.3–5.2) Overall survival by Prednisone dose Overall survival by Prednisone dose

The analysis of this data to date suggests the PSE dose at 3 months may be an important independent clinical marker for subsequent CGVHD prognosis which could be used to decide which patients to include in 2nd line and experimental therapy trials.
Obesity Does Not Impact Outcome in Patients with AML/MDS Undergoing Allogeneic Transplantation.
Authors: De Padua Silva Leandro , Saliba Rima M. , de Lima Marcos , Okoroji Grace J. , Alousi Amin , Andersson Borje , Hosing Chitra , Sphall Elizabeth , Khouri Issa , Qazilbash Muzaffar , Anderlini Paolo , Kebriaei Partow , Champlin Richard E. , Jones Roy , Giralt Sergio , Popat Uday
Published: April 2020

Background: Impact of obesity on transplant outcome is unknown. We hypothesized that obesity increases allogeneic transplant related morbidity/mortality. We therefore performed a case control study of obese patients with AML and MDS undergoing allogeneic transplant (AlloSCT) at our institution.

Patients and Methods: Sixty one patients with AML or MDS and a Body Mass Index (BMI) greater than 35 were transplanted from 1987 and 2006. 61 control patients were identified with BMI less than 30. The patients had similar characteristics. Controls were matched for age (within 5 years), disease status (relapse or remission), donor type (sib or MUD) and conditioning regimen.

Results: The median weight of obese patients was 109.5 Kg (range 78–151.3 Kg). Obese and controls had similar distribution of age (median age 47 years and 46 years respectively). Likewise gender, disease status, and cytogenetic risk groups were similar in the two groups. The majority (62%) of patients in both groups had IV Busulfan based conditioning therapy, while 11% had a TBI based regimen and 26% in both groups had reduced intensity conditioning with Fludarabine and Melphalan. Donor was a matched sib in 65% of cases and 66% of controls. The median time between transplant day and discharge was 23 days (range 14–98days) in both groups. Only significant difference between the two groups was the presence of comorbidites in obese patients. 75% of cases had a comorbidty score of 3 or more compared to 38% of controls (p<0.001) as defined by HCT index. Outcomes were similar in both groups. Two year non relapse mortality was 27% (95% CI: 18%-42%) in obese patients and 27% (95% CI: 17%- 41%) in control patients. Grade 3–4 toxicities occurred in 55% of cases compared to 42% of controls (p=0.2). Three-year disease free survival was 44% (95% CI: 31%- 57%) and 42% (95% CI: 29%- 55%) respectively in cases and controls. Median overall survival was 18 months for obese patients and 26 months for controls; 3-year overall survival was not significantly different in the two groups: 45% (95% CI: 31%- 58%) and 45% (95% CI: 31%- 58%) respectively for cases and controls.

Conclusion: Despite the higher prevalence of comorbidities in obese patients, obesity did not impair outcome in patients with AML/MDS undergoing AlloSCT. Hence, obesity should not be considered a contraindication to AlloSCT.