bluuebunny/crossref_metadata_2025 huggingface dataset:
Recommended Repeated Intrathecal Ara-C/MTX/PDN Injections during Rituximab-Based Therapy for B-Cell Lymphoma.
Authors: Wakao Daisuke , Suzuki Toshiya , Ito Katsuro , Yoshida Katsuhiko , Jinnai Itsuro , Bessho Masami
Published: October 2019

Rituximab-based chemotherapy for B-cell lymphoma is available in Japan since ‘01. We have treated twenty-eight B-cell lymphoma patients with rituximab and found four patients relapsed with posterior radiculopathy of the spinal cord due to lymphoma involvement. Because frequency of CNS lymphoma is reported to be 1~2%, we are surprised at the high incidence (14.2%) and thereafter we routinely repeat intrathecal cytarabine (Ara-C), methotrexate (MTX), and prednisolone (PDN) administrations during rituximab-based chemotherapy. Up to now, there is no new spinal cord relapse. The followings are the four spinal cord relapse cases we have experienced, which are characterized by severe back pain. (Case 1) A 46-years-old male with follicular lymphoma. Clinical stage (CS) was IIIB. He had cervical lymphadenopathy and breast involvement. He was treated with three courses of CHOP chemotherapy and achieved CR. Then he was treated with 1 course of rituximab alone and relapsed with severe neck and back pain five-days later. MRI imaging revealed posterior radiculopathy of the spinal cord between C2 and C4. (Case 2) A 48-years-old female with diffuse large B-cell lymphoma, CS IIIA. She had uterine cervix lymphoma and cervical lymphadenopathy four-years after acute lymphocytic leukemia (ALL) therapy. She was treated with 8 courses of biweekly R-CHOP and achieved CR. She relapsed with severe back and left arm pain with double vision six-months later. MRI imaging revealed posterior radiculopathy of the spinal cord between C5 and C6, and Th2 and Th3. She also had trigeminal radiculopathy and facial nerve oppression. The involved nerves were swollen like dumbbell. (Case 3) An 83-years-old female with MALToma, CSIIA. She had cervical lymphadenopathy. She was treated with 5 courses of rituximab alone and relapsed with severe back and lumbar pain one-month later. MRI imaging revealed posterior radiculopathy of the spinal cord between Th6 and Th7, and, Th12 and L1. (Case 4) A 63-years-old male with mantle cell lymphoma, CSIIIB. He had general lymphadenopathy. He was treated with 8 courses of CHOP, achieved CR, and relapsed with general lymphadenopathy and breast involvement thirteen-months later. He was treated with additional 7 courses of R-CHOP and relapsed again with severe oral, bilateral leg, and back pain seven-days later. MRI imaging revealed posterior radiculopathy of C2 and sacrum. All the patients except case 3 died due to lymphomas. When we treated the four patients with rituximab-based therapy, we did not repeat intrathecal Ara-C/MTX/PDN injections. Our data suggest that rituximab possibly induce posterior radiculopathy of spinal cord lymphoma involvement via some unknown pathway. In conclusion, we recommend repeated intra-thecal injections during rituximab administration.
Echocardiography Identifies Changes in Left Ventricular Cardiac Function after Low Doses of Anthracycline, Particularly in Older Patients.
Authors: Kruger Anton R. , Mepham Sophie , Belham Mark
Published: October 2019

Anthracyclines remain an essential component of treatment regimes for lymphoma. Increasing numbers of older patients are being offered potentially curative treatment for lymphoma and a corresponding increase in cases of cardiac toxicity might be expected. Upper limits for total doses of anthracycline are published, but there is little information on whether age predicts independently for cardiac susceptibility to anthracyclines. There is also little data on the effect of low doses of anthracycline on the heart. We have prospectively studied cardiac function in patients receiving Doxorubicin (DOX) for High Grade Non Hodgkin’s Lymphoma and Hodgkin’s disease. 28 patients are included: 18 male, 9 female aged 16 to 89 (median 59) years. Echocardiographic examinations were undertaken before and after patients received DOX at a median dose of 85 mg/m2 (50 mg/m2 to 150 mg/m2). The Left Ventricular (LV) Tei index was calculated in all cases as the sum of the isovolumetric contraction time and isovolumetric relaxation time divided by the ejection time. Higher values represent cardiac dysfunction and a rise post treatment was regarded as deterioration in LV function. For the group, there was a significant post treatment deterioration in LV function as measured by the Tei index: 0.400 ± 0.12 pre-treatment to 0.475 ± 0.16 post treatment (P = 0.0076). Multivariate analysis of age, pre-treatment Tei index and DOX dose (in this low range) revealed age to be the only significant predictor of deterioration in cardiac function after treatment (correlation coefficient 0.69, p < 0.0001).

We conclude that measurable changes in cardiac function occur after very low doses of DOX and that these changes are more marked in older patients. Whether these changes will predict for further deterioration after higher doses of DOX and potentially predict for long term symptomatic cardiac dysfunction post therapy will require further study and follow up.
Surgical Complications in Patients Treated with Chemotherapy for Gastric Diffuse Large B Cell Lymphoma.
Authors: Spectre Galia , Libster Diana , Grisariu Sigal , Da’as Nael , Gimmon Zvi , Paltiel Ora
Published: October 2019

The management of patients with gastric lymphoma has undergone significant changes in the past few years, with a shift towards non-surgical treatment. However, surgical complications still occur in patients receiving chemotherapy. The rate of these complications is unknown. Our aim was to assess the frequency of bleeding, perforation and gastric outlet obstruction in patients with gastric diffuse large B cell lymphoma who received chemotherapy as a primary treatment for their disease. In this study we retrospectively reviewed files of patients with gastric diffuse large B cell lymphoma, who were diagnosed and treated in our medical center between 1990 and 2005. Results: 88 patients were diagnosed with gastric diffuse large B cell lymphoma of whom 73 were initially treated with chemotherapy, mainly CHOP or similar regimens. The remaining 15 patients were treated with gastrectomy, irradiation, or died before treatment could be initiated. 69 patients had primary lymphoma of the stomach, 4 had gastric involvement at relapse, one had transformed follicular lymphoma and one had post transplant lymphoma. 18 of 73 (25%) patients experienced surgical complications during the course of their treatment. Seven patients had gastric bleeding, of whom 3 were treated conservatively, one underwent angiography with embolization, one had a gastrectomy, and in two patients treatment was stopped due to bleeding and poor performance status. Nine patients had gastric outlet obstruction, of whom 3 were treated conservatively, 4 required surgery, 1 had repeated endoscopic pneumatic dilatations, and one stopped treatment. Seven of 9 patients had no evidence of active lymphoma at the time of gastric outlet obstruction. Two additional patients underwent gastrectomy, 1 due to resistant disease and 1 for relapsed disease. Gastric perforation was not observed. Overall 6 of 73 (8%) of patients eventually required gastric surgery; 3 are alive and free of disease, one died from lymphoma and two died from other causes. We conclude that there is a substantial rate of surgical complications in patients with gastric diffuse large B cell lymphoma receiving chemotherapy and thus, there is still a major role for the surgical consultant in the treatment of these patients. Gastric perforation is a rare complication.
High Resolution Computed Tomography of Bleomycin-Induced Lung Injury in Hodgkin Lymphoma.
Authors: Akay Meltem Olga , Ozkan Ragip , Uskudar Dondu , Gulbas Zafer
Published: October 2019

Bleomycin is the chemotherapeutic agent most commonly associated with pulmonary toxicity in about 4–20% of treated patients. The diagnosis of bleomycin-induced lung disease is primarily clinical and there is no true gold standart test available. In this study, we aimed to evaluate the role of high resolution computed tomography (HRCT) in monitoring patients for drug toxicity.

We prospectively evaluated the HRCT scans of 18 newly diagnosed hodgkin lymphoma patients baseline, after the fourth and the eight cycle of ABVD (Adriamycin-bleomycin-vinblastine-dacarbazine) chemotherapy. The age ranges of the patients was 17–69 years (mean, 35 years). Serial PFTs and arterial blood gases were obtained in addition to imaging studies during bleomycin therapy. The parenchymal abnormalities on HRCT were grouped into different categories according to the dominant pattern and distribution of disease: diffuse alveolar damage (DAD), nonspecific interstitial pneumonitis (NSIP), bronchiolitis obliterans organizing pneumonia (BOOP), interstitial pneumonitis and fibrosis and hypersensitivity reaction. Pulmonary parenchymal abnormalities were detected on HRCT in 5 of 18 patients (27.8%). Patient details, cumulative doses of bleomycin and patterns of lung injury are presented in table. Arterial O2 pressure (p<0.01), O2 saturation (p<0.01) and carbon monoxide diffusing capacity (DLCO) (p<0.01) were decreased after bleomycin therapy compared to baseline values in 18 patients.

Our results indicate that HRCT is useful in the diagnosis of bleomycin-induced lung disease by better characterization of the nature of the abnormality and assessment of extent and distribution of disease.

Bleomycin-induced lung disease No Age Sex Dose Pattern of lung injury 1 46 M 234 mg BOOP 2 30 M 128 mg NSIP 3 69 F 210 mg NSIP 4 26 M 162 mg BOOP 5 51 M 256 mg NSIP
Report of a Phase II Study of Proteasome Inhibitor Bortezomib (Velcade) in Patients with Relapsed or Refractory T-Cell Lymphoma.
Authors: Zinzani Pier Luigi , Tani Monica , Stefoni Vittorio , Alinari Lapo , Marchi Enrica , Fina Mariapaola , Baccarani Michele
Published: October 2019

The 26S proteasome plays a vital role in degrading regulatory proteins such as p53, p21, p27, NF-kB, I-kB, and bcl-2, that govern cell cycle, transcription factors activation, apoptosis and cell trafficking. Thus, the mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and the extent to which each affected pathway is critical to the inhibition of tumor growth could also differ. The aim of this study was to determine the efficacy and toxicity of bortezomib in previously pretreated patients with peripheral T-cell lymphoma unspecified (PTCLU) and cutaneous T-cell lymphomas (CTCL). Each patient had to meet the following inclusion criteria to be enrolled in the study: histologically confirmed PTCLU or CTCL (according to REAL/WHO classification); any stage, any IPI, any bone marrow status; second or more relapse or refractory disease; age ≥ 18; ECOG performance status ≤ 2; Hb ≥ 10 g/dL, ANC ≥ 1.5x109/L and platelets ≥ 100 x 109/L; normal hepatic, renal and cardiac functions; and voluntary written informed consent. Bortezomib was given at 1.3 mg/m2 IV push on days 1, 4, 8 and 11 every 21 days. Restaging was done every 2 cycles. Patients were treated for up to a total of 6 cycles unless removed from study for failure to respond or toxicity. The response criteria were those recommended by NCI sponsored Working Group. A total of 30 patients will be enrolled; so far 10 patients entered and preliminary results of this trial will be presented.
Comparison of Outcome of Unselected Patients with Diffuse Large B-Cell Lymphoma Diagnosed before and after Approval of Rituximab in France in This Indication.
Authors: Ghesquières Hervé , Sebban Catherine , Chassagne Catherine , Carausu Liana , Gargi Thérèse , Favier Bertrand , Philip Irène , Blay Jean Yves , Biron Pierre
Published: October 2019

Two randomized-controlled trials had demonstrated improved outcome with adding rituximab to CHOP for elderly patients and young low-risk patients with DLBCL (Coiffier et al., NEJM 2002 and Pfreundschuh et al., ASH 2004, abstr #88). It seemed interesting to assess whether this was confirmed in daily practice in an unselected patient population. We compared the outcome of newly diagnosed patients treated in our department between two time periods, before and after approval of rituximab for treatment of DLBCL in France, in March 2002. Patients with primary cerebral lymphoma, secondary transformation of indolent lymphoma or HIV positivity were excluded of the study but no selection was made on type of initial treatment or therapeutic intent (palliative or curative) to conform with daily clinical practice. 229 patients were identified, with median age 61 years (range, 20–90), elevated LDH (66%), extranodal sites >1 (26%), stage III-IV (57%), poor performance status >1 (24%), IPI score 0–1 (37%), 2 (20%), 3(21%), 4–5 (22%). 148 patients were diagnosed between 01/1996 and 03/2004 (time period 1) and 81 between 04/2002 and 07/2004 (time period 2). Patient characteristics did not differ between the two time periods (median age, performance status, stage, elevated LDH, extra-nodal involvement, IPI distribution). 11% of patients received rituximab as part of initial treatment in time period 1, and 93% in time period 2. Response rates at the end of treatment for time periods 1 and 2 were CR/CRu 71% and 79% (p=0.1), PR 6% and 10% (p=0.3), progression 17% and 9% (p=0.08), toxic death 6% and 2% (p=0.2), respectively. At the time of this abstract, the follow-up for living patients was 60 and 18 months for time periods 1 and 2 respectively, with no difference in terms of progression-free survival (PFS), event-free survival (EFS) and overall survival (OS). The lack of outcome difference between the two cohorts could be due to short follow-up of time period 2 and efficiency of rituximab in the patients treated in time period 1. In fact, PFS is significantly improved for patients under rituximab compared to patients not treated with rituximab (see survival outcomes in table). In conclusion, this global evaluation of treatment with rituximab in an unselected population of DLBCL patients before and after date of approval of rituximab requires further follow-up for validation of outcome benefit.
An Applicational Observation of Low-Dose Rituximab in Elderly Patients with Nodal Marginal Zone Lymphomas.
Authors: Roggero Enrico , Palumbo Antonella , Di Martino Stefania , Busi Giancarla , Pedrazzini Augusto
Published: October 2019

Background: Single-agent rituximab was shown to prolong overall response rate (ORR) in marginal zone lymphomas. However, despite the confirmed activity of this immuno-biologic agent a significant number of adverse events were reported in this commonly considered indolent lymphoma entity.

Methods: To reduce the impact of rituximab toxicity we investigated the activity of low-dose rituximab infusions in 3 consecutive elderly patients (over 70 years) with nodal marginal zone lymphomas. All patients (Ann Arbor stage IV with bone marrow (BM) involvement, age range from 71 to 84 years, normal LDH and WHO performance status = 0) were treated with weekly low-dose rituximab (75 mg/m2) administred for 6 consecutive weeks.

Results: All patients complleted the treatment program. No complete response were observed. All patients confirmed a partial response (PR) with reduction of symptoms and disease related BM involvement. The median response duration was 14 months. At a median follow-up of 18 months, 2 patients relapsed and one patient (chemiotherapy naive) is still responding. The 3 patients did not experienced any adverse events and depsite the older age of patients, no expected infusion-related side effects were recorded.

Conclusion: This investigative report demostrated the efficacy and the well tolerability of low-dose rituximab (75 mg/m2 administreted weekly for 6 consecutive weeks) in elderly patients with well defined diagnosis of nodal marginal zone lymphoma. These observations can lead to the hypothesis that the dose and the schedule of rituximab should be redefined in this lymphoma entity.
R-CHOP in the Treatment of DLBCL: Single Institution Experience from North India.
Authors: Vaid Ashok K. , Gupta Sachin , Doval Dinesh C. , Talwar Vineet , Gupta Rajeev , Sharma J. B. , Chaturvedi A. K. , Prakesh Neeraj
Published: October 2019

Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of NHL. Different chemotherapy regimens tested in the past showed RR of appx 80% with no improvement in prognosis & OS. CHOP regimen has been the standard treatment for these patients (pts). Rituximab has improved response rates & survival in CD20 positive lymphoma pts, especially elderly (GELA trial: CR 73% vs. 63%). We retrospectively evaluated pts of DLBCL treated with R-CHOP regimen between April 2001 & June 2005. All pts had biopsy and IHC of lymph node/extranodal site, & CT scan of neck, chest, abdomen; BM biopsies; CBC, serum chemistries; 2D echocardiography/MUGA scans. All pts received Rituximab (375mg/m2) & CHOP 3 weekly for a maximum of 8 cycles. Pts who received at least 1 & 3 cycles of R-CHOP were evaluable for toxicity and response respectively. In total, 36 pts were included for analysis. The median age was 53 years, 10/36 pts (27.8%) were >60 years. 25/36 were male (69.4%). ECOG performance status: 0–1 in 30/36, and 2–4 in 6/36. 11/36 had B-symptoms, 16/36 had high LDH, 6/36 had bulky disease. Extranodal involvement was present in 19/36; 10/36 had ≥2 sites of extranodal involvement. Lymph nodal swelling was most common presentation in 24/36 (66.7%), followed by pain 10/36 (27.8%), weight loss 9/36 (25%), fever 7/36 (19.4%), skin nodules 3/36 (8.3%). Extranodal sites were: bone marrow 5/36, bone 4/36, skin 3/36, GIT 3/36, pleural effusion 2/36, lungs 2/36, other soft tissue 2/36, and parotid, nasopharynx, orbit, adrenal, testes, kidneys-1 each. Gallium scan at base line, done in 12/36, was positive in 11 pts (91%). Stage distribution was as follows: stage-I none, stage-II 10/36 (27.8%), stage-III 13/36 (36.1%), stage-IV 13/36 (36.1%). IPI scoring was-low risk 13/36 (36.1), low intermediate 9/36 (25.0%), high intermediate 13/36 (36.1) & high risk 1/36 (2.8%). A total of 199 cycles of R-CHOP were administered with a median of 6 cycles per patient. Of the 33 pts evaluable for response, 22 achieved CR (66.7%), 9 PR (27.3%), 1 each SD & PD. There were 2 treatment related mortalities. Toxicities were: grade III/IV neutropenia in 12/36 (33.3%), thrombocytopenia 4/36 (11.1%), peripheral neuropathy 2/36 (5.6%). Mild hypersensitivity to Rituximab was seen in 2/36 (5.6%) pts. Only 1 patient had cardiac toxicity in form of CHF. Our study showed response rates (94%) and toxicity profile similar to what has been reported in other studies with R-CHOP. The follow-up is too short to evaluate survival rates. Keywords: DLBCL, Rituximab, CHOP.
Phase I Clinical Study of Imatinib Mesylate in Combination with Tetra-Arsenic Tetra-Sulfide in the Treatment of CML Patients in Advanced Phase.
Authors: Li Junmin
Published: October 2019

OBJECTIVE: We performed a Phase I study to evaluate the toxicity and potential efficacy of Imatinib Mesylate (Glivec) in combination with Tetra-arsenic tetra-sulfide (As4S4) in patients with advanced CML.

PATIENTS AND METHODS: Ten CML patients in advanced phase were enrolled in this study. All patients received imatinib with As4S4 150mg/kg/d (day 1–14, each month) for 6 months. The initial dose of imatinib was 400mg/d in first 3 patients, with subsequent escalation to 600mg/d in other 7 patients. Adverse events and potential hematological, cytogenetic and molecular response was closely monitored. A concurrent control group of 10 patients received imatinib monotherapy at 600mg/d was included for the analysis of toxicity profile and clinical efficacy.

RESULTS: From Dec.2003 to Jun.2004, a total of 10 patients (6 males and 4 females with median age at 33.5) were enrolled in this trial, in which 5 in accelerated phase(AP)and 5 in blast crisis (BC). There were no significant differences in base-line characteristics between the study group and the concurrent control group. Non-hematologic toxicities such as gastrointestinal discomfort, edema, liver dysfunction and myalgia/bone pain were common and mild (Grade 1/2). Grade 3 or 4 hematologic toxicities, including neutropenia, thrombocytopenia and anemia, occurred in 3 patients. There was no difference in either hematological or non-hematological toxicities between the study and the control group. The patients in both group had equivalent complete hematological response (CHR= 70%) and complete cytogenetic response (CCR= 30%) rates. All 3 patients in the study group with CCR achieved more than 3 log reduction of BCR-ABL transcripts level while only one patient obtained a molecular response in control group. With a median follow-up of 14 months (2 to 18 months) in both group, the patients in study group showed a similar overall survival (1yr OS 68.6%±15.2%) and a slight better progress free survival (1yr PFS 75.0%±17.3%) compared to concurrent control group (1yr OS 70.0%±14.5% and 1yr PFS 50.5%±17.7%). Of notice, all patients with cytogenetic and molecular response did not have additional cytogenetic abnormality besides the Ph chromosome before the treatment.

CONCLUSIONS: The combination therapy with 600mg daily imanitib and 150mg/d As4S4 is safe and feasible for advanced CML patients. Though patients with additional cytogenetic abnormality were unlikely to response to the combination therapy, complete hematological, cytogenetic and even molecular response was documented in the advanced CML patients with combination therapy. The primary data suggested a potential clinical benefit in patients with advanced CML, thus clinical trial to further test in chronic phase CML without additional cytogenetic abnormality will be warranted.
Retrospective Analysis of Weekly Administration of Bortezomib in Multiple Myeloma.
Authors: Sayar Hamid , Lee Fa-Chyi
Published: October 2019

Background: Currently the standard treatment of multiple myeloma (MM) with the proteasome inhibitor bortezomib (Velcade) is by twice weekly administration of the drug. We present a retrospective study of bortezomib therapy by weekly dosing in MM patients unable to tolerate the standard regimen.

Methods: Since January 2004, five patients (3 male and 2 female, age 47 – 81) have been treated at our center by weekly, and one (male, 86) by every-two-week administration of bortezomib. This approach was selected primarily due to low performance status and/or comorbidities. All patients had failed at least one prior treatment modality. Each cycle of the weekly schedule consisted of one dose every week for two weeks, followed by two weeks of rest. Mainly for convenience purposes, two patients while stable on weekly treatment, were switched to even less frequent treatment of once every-three-weeks. Furthermore, five patients received a plain dose of 2.0 mg rather than regular dose calculation per body surface area.

Results: All 5 patients on weekly schedule had an initial moderate to major response, followed by a stable course. None of them, however, achieved a complete remission. 2/5 demonstrated progression of disease after they were switched to every-three-week dosing. The patient on every-two-week treatment had an initial favorable response, and is currently being switched to the weekly schedule due to excellent tolerance.

Conclusion: Our retrospective analysis indicates that weekly bortezomib therapy is a promising alternative approach to the treatment of MM in those patients intolerant to standard regimen. It seems reasonable, therefore, to attempt a larger prospective study of bortezomib administration with less frequent dosing, mainly in this group of MM patients.
A Phase I Study of Talvesta® (Talotrexin) in Relapsed or Refractory Leukemia or Myelodysplastic Syndrome.
Authors: Giles Francis , Rizzieri David A. , George Solly , Stock Wendy , Fontanilla Jeannie , Choy Gavin S. , Berk Gregory I.
Published: October 2019

Talvesta® is a novel, nonpolyglutamatable antifolate drug which has demonstrated improved antitumor activity in a broad spectrum of cancer models by targeting DHFR to inhibit tumor growth. Talvesta binds more tightly to DHFR than methotrexate (MTX), with a Ki of 0.35 pM, which is 15-fold lower than MTX. Talvesta enters cells by the reduced folate carrier (RFC) pathway. In CCRF-CEM leukemia cell lines, Talvesta compared to MTX exhibited an IC50 of 1.1 nM and 11 nM, respectively. An open-label, dose escalation study of Talvesta administered as a 5–10 minute infusion on Days 1–5 on a 21-day cycle to patients with relapsed or refractory leukemias is ongoing. The primary objectives of this study are to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT), and evaluate the pharmacokinetics, safety and efficacy. Patients with AML, ALL, CLL, CML-BP, MDS, RAEB or RAEBT and CMML for whom no standard therapy resulting in a durable remission is available and with an ECOG PS 0–2, were enrolled. The starting dose was 0.2 mg/m2 (1 mg/m2 per cycle) based on preclinical data with dose escalation based on a modified Fibonacci sequence. Three patients were treated at each dose level in the absence of a DLT. All patients received folic acid and B12 vitamin supplementation. Plasma Talvesta concentrations were analyzed by a validated LC/MS/MS method during cycle 1. To date, twenty-two (22) (16 male) heavily pre-treated patients (11 AML, 7 ALL, 1 CML-BP, 2 CLL, 1 Hairy Cell) median age 52 years (range, 19–84) have been enrolled and received a total of 29 cycles of Talvesta (median 1, range 1–4) at doses of 1 mg/m2 to 4 mg/m2 per cycle. Two patients experienced neutropenic fevers possibly/probably related to talvesta administration. Dose escalation continues in an attempt to identify a DLT with subsequent initiation of a Phase II study in patients with refractory ALL. One major response has been observed in a patient with refractory ALL. Pharmacokinetic parameters are pending analysis. Talvesta at the tested doses in this heavily pretreated leukemia patient population has been well tolerated.
Reduced-Intesity Allogeneic HSCT in Hematologic Malignancies: Influence of Underlying Diagnosis and Prior Autograft on Outcome.
Authors: Mehta Jayesh , Gordon Leo , Tallman Martin , Winter Jane , Williams Stephanie , Frankfurt Olga , Evens Andrew , Grinblatt David , Kaminer Lynne , Meagher Richard , Rashid Kamran , Grabowski Donna , Singhal Seema
Published: October 2019

RI-HSCT is now accepted practice in a number of clinical scenarios. However, two circumstances in which it is still often not covered by insurance carriers is a diagnosis of acute leukemia (AL) and relapse following an autograft. The aim of this analysis was to specifically study the influence of these 2 factors in the context of known prognostic variables in a series of 91 uniformly-treated patients with hematologic malignancies (19–71 years; median 53; 22% >60 years). 41 had relapsed after a prior autograft (6/29 AL, 20/38 lymphoma, 15/24 myeloma; P=0.005). 62% had refractory disease. Performance status (PS) was 0 in 31%, 1 in 47%, and 2/3 in 22%. Donors (55% >45 years) were HLA-matched siblings (n=51), 10/10 allele-matched unrelated (n=29), or 9/10 allele-matched (n=11). The conditioning comprised 100 mg/m2 melphalan with (no prior auto) or without (prior auto) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised cyclosporine-mycophenolate (HLA-matched sibs) or tacrolimus-mycophenolate (others). G/GM-CSF were not given routinely. Supportive care was uniform. As the table below shows, the 2-year cumulative incidence of relapse and non-relapse mortality (NRM) and 2-year disease-free (DFS) and overall (OS) survival rates were not significantly influenced by the diagnosis or prior autograft.

Relapse NRM DFS OS Acute leukemia 55% 22% 23% 37% NHL/Hodgkin 42% 29% 28% 47% Myeloma 66% 18% 16% 36% P 0.35 0.49 0.89 0.51 No prior autograft 48% 26% 25% 39% Prior autograft 60% 21% 19% 42% P 0.82 0.55 0.88 0.52

Next, diagnosis and prior autograft were entered into a Cox model with chemosensitivity, donor age, LDH and PS; variables known to influence outcome significantly in this group of patients. The 4 known variables retained their significance in influencing OS (LDH P=0.001, chemosensitivity P=0.003, PS P=0.003, donor age P=0.01) and DFS (chemosensitivity P=0.002, PS P=0.02, donor age P=0.02, LDH P=0.03). Prior autograft did not influence OS (P=0.77) or DFS (P=0.57) as shown in the figure below (derived from the Cox model; adjusted for the 4 significant variables).

Figure Figure

Diagnosis did not influence DFS (P=0.49). However, it did affect OS (overall P=0.04; AL vs myeloma P=0.23; AL vs lymphoma P=0.01; myeloma vs lymphoma P=0.25) as shown in the figure below (derived from the Cox model; adjusted for the 4 significant variables.

Figure Figure

The difference in OS likely reflects the fact that unlike for lymphoma and myeloma, salvage therapy is of limited benefit for AL relapsing after HSCT. However, comparable DFS suggests that the extent of benefit provided by the RI-HSCT procedure itself is independent of diagnosis. We conclude that prior autograft or the underlying diagnosis should not be used to determine eligibility for RI-HSCT.
The Proteasome Inhibitor NPI-0052 in Combination with Bortezomib Induces Antitumor Activity in Waldenstrom Macroglobulinemia.
Authors: Jia Xiaoying , Leleu Xavier , Moreau Anne-Sophie , Hatjiharisi Evdoxia , Ngo Hai , O’Sullivan Garrett , McMillin Douglas , Treon Steven , Mitsiades Constantine , Hideshima Teru , Palladino Michael , Anderson Kenneth , Chauhan Dharminder , Ghobrial Irene
Published: October 2019

Background: Waldenstrom’s Macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma. Recently, Bortezomib has demonstrated clinical activity in patients with relapsed WM. The purpose of this study was to investigate the in vitro effect of the new proteasome inhibitor NPI-0052 (Nereus Pharmaceuticals, CA), alone and in combination with Bortezomib, in WM.

Methods: WM cell lines (BCWM1 and WSU-WM) and IgM secreting low-grade lymphoma cell lines (MEK1, RL, Namalwa) were used. Bone marrow primary CD19+ malignant cells were obtained from WM patients after informed consent. Inhibition of growth was measured using MTT assays. DNA synthesis was measured using the thymidine incorporation assay. Apoptosis was determined using Apo2.7 staining, followed by flow cytometric analysis. Determination of the additive or synergistic effect of the combination was calculated using the CalcuSyn software (Biosoft, MO) based on the Chou-Talalay method with the combination index (CI)<1.0 indicating synergism.

Results: NPI-0052 induced cytotoxicity and inhibition of DNA synthesis, with an IC50 of 20–30nM in all cell lines tested at 24 hrs. NPI-0052 induces 50% apoptosis at 48 hrs. Similar effects were demonstrated in primary CD19+ WM cells. Bortezomib induced cytotoxicity and inhibition of DNA synthesis with an IC50 of 20–30nM in all cell lines tested. Importantly, the combination of NPI-0052 and Bortezomib induced significant inhibition of proliferation compared to each agent alone, specifically at the combination of 2.5nM and 5nM of Bortezomib and 10nM of NPI-0052. For example, Bortezomib single agent at 2.5nM and 5 nM induced 8% and 13% cytotoxicity in BCWM.1 in vitro, respectively, while the combination Bortezomib and NPI-0052 10nM induced a synergistic cytotoxic effect, 44% (CI=0.7) and 58% (CI=0.47), respectively. The combination effect of NPI-0052 20 nM with Bortezomib 2.5nM and 5nM was also synergistic, with 61% (CI=0.7) and 66% (CI=0.7) cytotoxicity, respectively. Similar effects were observed in 3 primary CD19+ WM cells obtained from patients’ bone marrow.

Conclusion: NPI-0052 has significant anti-tumor activity against WM in vitro, especially in combination with Bortezomib. These results provide the framework to further study the potential therapeutic role of NPI-0052 in WM. *XJ and XL are co-first authors.
Bortezomib Once Weekly Is Well Tolerated as Maintenance Therapy after Less Than a Complete Response to High-Dose Melphalan in Patients with Multiple Myeloma.
Authors: Knop Stefan , Hebart Holger , Kunzmann Volker , Angermund Ralf , Einsele Hermann
Published: October 2019

Background: Despite intensive treatment strategies in multiple myeloma (MM) consisting of one or two cycles of high-dose melphalan (HD-Mel) with autologous stem cell support only a minority of patients (pts) achieves molecular complete remission leading to an event free survival (EFS) of eight to ten years. The median EFS for all patients following HD-Mel, however, is no more than 30 to 35 months. Several agents have been evaluated as a part of maintenance strategies in order to eradicate minimal residual disease and thus extending the period until salvage treatment is required. Interferon alpha, that has been most widely used in this setting showed a significant prolongation of EFS and a trend to better overall survival in a large meta-analysis. Bortezomib (VELCADE® [Vel]), a proteasome inhibitor, has substantial anti-myeloma activity in relapsed and refractory disease and was shown to induce exceptional response rates, including consistently high CR rates in up-front treatment.

Patients and methods: We decided to set up a phase II trial in patients up to 70 years with less than CR (SD, PR, or VGPR) after one or two cycles of HD-Mel using a less dose-intense schedule than the standard protocol for monotherapy. The first eleven pts were to receive four cycles of Vel 1.0 mg/m2 once weekly for four weeks followed by a two-week rest period. Since no dose limiting toxicity occurred, the dose was increased as per protocol to 1.3 mg/m2 for the subsequent pts.

Results: Up to now, 20 subjects were included with a median age of 60.5 (range, 46 – 69) years, 3 of whom had previously received single, and 17 tandem HD-Mel. Two cases of moderately severe herpes zoster prompted us to generally administer acyclovir prophylaxis throughout the treatment. Five pts experienced symptoms of peripheral neuropathy all of which were of grade I. WBC nadir occurred during cycles 2 and 3 with a median of 3.7 × 109/l while median PLT and HB values did not decline below normal values. Three patients progressed while on the study and received salvage treatment while all other patients enrolled completed all four scheduled cycles of treatment. To date, two patients showed improvement of response by conversion of VGPR into CR with confirmed negative immunofixation.

Conclusion: We are currently continuing patient accrual on the once-weekly 1.3 mg/m2 schedule since treatment is considered to be safe. Data on the efficacy (i.e. median EFS, OS as compared to historic controls on interferon alpha), however, will require significantly longer follow up.
N-Acetylcysteine Mildly Inhibits the Graft vs Leukemia Effect but Not the Lymphokine Activated Cells (LAK) Activity.
Authors: Shapira Michael Y. , Weiss Lola , Reich Shoshana , Zeira Michael , Slavin Shimon
Published: October 2019

N-acetylcysteine (NAC) is a known antioxidant and induces modulation of glutathione cellular content effects. It has been suggested that in the context of stem cell transplantation (SCT), NAC was suggested as a possible agent in order to prevent and treat graft-vs.-host disease, veno-occlusive disease and idiopathic pneumonia syndrome. We investigated the possible effect of NAC on graft-vs.-leukemia effect (GVL) and lymphokine activated cells (LAK) activity in murine models. After 10 days of either oral or intraperitoneal NAC treatment, the cytotoxic activity of the LAK cells against Yac cells (H-2a, NK sensitive tumor cell line)did not significantly differ from LAK activity generated from spleen cells obtained from untreated controls. However, NAC mildly suppressed GVL (appearance of BCL1 leukemia in 8/36 animals treated with NAC as compared to 0/20 in the transplantation control group, p=0.023, figure 1). In spite of this mild suppression of GVL, no negative effect on engraftment, judged by achievement of donor chimerism, was seen.

We conclude that NAC usage in SCT maybe relatively safe in regard to the GVL effect, yet further clinical studies are warranted.

Figure Figure
B Cells Suppress IL-2, IFN-γ and TNF-α Production from Alloaggressive CD8+ T Cells in a Mismatched Murine Model of Bone Marrow Transplant.
Authors: Ritchie David S. , Watt Victoria
Published: October 2019

B cells have been variously shown to induce direct tolerance of antigen specific CD8+ T cells in models of autoimmunity and tumor immunology. We have previously shown that resting B cells also inhibit anti-tumor T cell function and suppress graft versus host disease (GVHD) in a mismatched mouse model. We have extended these findings to reveal that B cell depletion of the donor graft results in more rapid T cell engraftment and higher IL-2, IFN-γ and TNF-α production by engrafting alloagressive T cells. In turn the degree of cytokine production was highly correlated with the degree of weight loss in mice developing GVHD underscoring the importance of T cell derived inflammatory cytokines in the development of GVHD. Conversely, those mice treated with additional resting B cells at the time of marrow infusion showed lower levels of cytokine production from engrafting T cells and subsequently less GVHD. Further, the amount of INF-γ and TNF-α production from alloaggressive T cells post transplant was substantially greater when a donor splenocytes we used to supplement bone marrow. The clinical score and histological examination of mice undergoing splenocyte + bone marrow transplant showed substantially differences compared to that observed in the bone marrow only model The post splenocyte transplant model reflected a hyperacute GVHD syndrome as opposed to clinically relevant, histologically proven acute GVHD derived from the transplant of bone marrow and furhet indicate that rapid disregulated T cells engraftmnet of central to the onset of devastaing GVHD. These findings indicate that resting B cells may regulate T cell engraftment and activation through regulating T cell homeostasis and suppression of inflammatory cytokines. B cells therefore may potentially be used therapeutically to limit GVHD mediated by alloaggressive T cells, whilst profound pre-transplant depletion of B cells may be detrimental to transplant outcome due to the promotion of GVHD.
The Comparison of In Vitro and In Vivo Anti-Host Responses as a Predictor of T Cell Reactivity after Allogeneic-BMT as Determined by TCR Vb Spectratype Analysis.
Authors: Friedman Thea M. , Azhipa Olga Y. , Filicko Joanne , Mookerjee Bijoyish , Flomenberg Neal , Donato Michele L. , Rowley Scott D. , Korngold Robert
Published: October 2019

Immunotherapeutic strategies have gained recognition as viable alternatives to more conventional therapeutic modalities for the treatment of cancer. In this regard, adoptive T cell therapy through allogeneic blood and marrow transplantation (BMT) has offered the first evidence to demonstrate that anti-tumor effects could be achieved against hematological malignancies. However, complications which include graft failure, opportunistic infections, leukemic relapse and graft-versus-host disease (GVHD) underscore the importance for the development of more targeted strategies in order to promote the successful implementation of allogeneic-BMT as a long term curative approach. It is well understood that mature donor T cells present in the donor inoculum must be an integral part of any such strategy as they play a pivotal role in all of the above mentioned complications. The incidence of the first three complications is diminished by the presence of mature donor T cells while, unfortunately, the transplantation of mature alloreactive donor T cells also directly induces the latter complication of acute GVHD, which can be directed against either HLA or minor histocompatibility antigen (miHA) disparities. Efforts to pan deplete donor marrow inoculum of T cells have been successful in minimizing the development of disease but have been associated with increased leukemic relapse. Thus, one approach to solve this problem would be to identify and then selectively deplete alloreactive donor T cells while allowing the residual T cells to provide protection against infection and to mediate a leukemia-specific GVL response. We hypothesized that an in vitro culture system using a one-way mixed lymphocyte reaction generated between a potential allogeneic BMT donor and their respective recipient could give rise to many of the alloreactive T cell responses that would be predictive of those that would be generated in vivo, following BMT. We proceeded to test the predictive value of the in vitro culture system through the use of TCR CDR3 Vβ spectratype analysis in the clinical BMT setting. To this end we compared, by spectratype analysis, the in vitro and post-transplant in vivo responses of nine donor patient pairs. The results indicated a high association of overlapping Vβ CDR3-size skewing as defined by the reactive Vβ families in the patient post-transplant also found to be reactive in the in vitro culture system (range of overlap 50–100%, median 72.5%). Thus, in vitro spectratyping analysis may be useful in guiding the manipulation of the donor T cell inoculum in order to provide improved BMT outcomes.
In Vitro Methotrexate: A Practical Approach to Selective Allodepletion.
Authors: Sathe Atul , Ortega Sterling , Mundy Dorothy , Collins Robert H. , Karandikar Nitin J.
Published: October 2019

Graft-versus-Host Disease (GvHD) remains a major cause of transplant-related morbidity and mortality in recipients of allogeneic hematopoietic stem cell transplantation (AHSCT). Selective depletion of alloreactive T-cells may alleviate GvHD, while still maintaining other advantages conferred by donor T-cells, such as graft survival, antiviral immunity and graft-versus-leukemia effect. While several strategies for in vitro allodepletion have been proposed, their transition from pre-clinical studies to clinical use is sometimes hindered due to choice of reagent or technique. In this study, we evaluated the potential use of methotrexate (MTX), an FDA-approved drug known to inhibit T-cell proliferation, as an agent for specific in vitro allodepletion. Using a sensitive, flow cytometry-based proliferation assay, we first evaluated the effect of MTX on CD4+ and CD8+ T-cell proliferation in an HLA-mismatched one-way MLR. Addition of MTX resulted in significant inhibition of both CD4+ and CD8+ T-cell proliferation in MLR as well as superantigen-stimulated control reactions (n=14; p<0.001). We next evaluated whether this exposure to MTX resulted in selective allodepletion. Thus, live cells isolated from MTX-exposed MLR cultures were re-exposed to multiple stimuli, including the same allostimulus, a third-party allostimulus, cytomegalovirus (CMV) antigen and the superantigen SEB. We observed that CD4+ and CD8+ T-cell responses to same allo-stimulus were significantly abrogated, whereas T-cell responses to third-party stimuli, CMV and SEB were all preserved (n=12; p<0.01). These results provide strong pre-clinical evidence that in vitro treatment with MTX, a practical FDA-approved agent, results in specific allodepletion and may be used as an effective approach for preventing or minimizing GvHD.

Inhibition of alloreactive T-cell proliferation by MTX Inhibition of alloreactive T-cell proliferation by MTX Loss of response to same allostimulus with preservation of “third party” and anti-viral responses in MTX-treated T-cells Loss of response to same allostimulus with preservation of “third party” and anti-viral responses in MTX-treated T-cells
Outcome of Patients with Aplastic Anemia Given First Line Transplantion or Immunosuppression in the Last Decade: A Report from European Group for Blood and Marrow Transplantation (EBMT).
Authors: Locasciulli Anna , Oneto Rosi , Bacigalupo Andrea , Socié Gerard , Korthof Elisabeth , Bekassy Albert , Schrezenmeier Hubert , Passweg Jakob , Fuhrer Monika
Published: October 2019

Background Changes have occurred in the treatment of acquired severe aplastic anemia (SAA) over the past decade,and the optimal treatment for children and adults is often debated.

Aim of the study. Aim of this study was to assess whether the outcome of patients with SAA has improved in two sequential time periods, 1990–1995 and 1996–2002.

Patients and methods., We analyzed a total of 2479 consecutive patients with SAA classified according to first line treatment: allogeneic bone marrow transplantation (BMT) (n=1567) or immunosuppressive therapy (IS) (n=912), and stratified for age (</=> 16 years).

Transplantation. The overall actuarial 5 year survival was 74% before 1995 and has not change overall (it is currently 75%). Survival was improved in the two time periods, for patients given first line BMT (69% vs 79%, p=0.001) but not in patients given first line IS (76% vs 72%, p=0.3). In the latter patients there was a confounding effect of disease severity: patients with very severe AA (neutrophils <200) improved their autcome after IS therapy in the two time periods though not significantly (72% vs 82%, p=0.1); patients with SAA (neutrophils 200–500) had superimposable outcome (76%) and patients with non severe AA actually had worse outcome in the most recent period (77% vs 55%, p=0.01). Overall improvement was significant in children (p=0.02) but not in adults (p=0.4). In multivariate COX analysis negative predictors of survival were a long interval between diagnosis and first treatment (>50 days, RR 1.5, p=0.00001) and age > 16 (RR1.5, p=0.0001).

Interpretation and conclusions. This study shows that outcome has improved in the past decade in subsets of patients with SAA: BMT patients and IS patients if they have very severe aplasia. Early intervention should be reccommended in all patients, whathever the first line therapy, due the very strong effect of interval between diagnosis and treatment on survival.
The LTB4 Receptor Is Involved Not Only in the Downstream Pathway of rh-GCSF Mobilization but in the LTB4 Mobilization Pathway in C57BL/6 Mice.
Authors: Mun Yeung-Chul , Lee Seung-Eun , Lee Kyoung-Eun , Yoo Eun-Sun , Lee Sang Min , Kong Jee Hyun , Ahn Jee-Young , Bae Yun-Kyung , Lee Soon-Nam , Kim Jae-Hong , Seong Chu-Myong
Published: October 2019

Though we were able to shorten the CD34+ cell mobilization by 24~48h by using continuous intravenous rhG-CSF rather than SQ rhG-CSF, it still will take several days when used normal individuals (Lee et al, BMT2005, 36:1027–1031). Previously we had reported that LT(Leukotriene)B4 was able to mobilize HSC in the murine model within 4 hours without significant side effects(ASH 2005). However, because there are possibilities of similar mechanisms during the HSC mobilization, which are shared by rhG-CSF or LTB4, in this study, we investigated the role of LTB4 receptors by rhG-CSF during HSC mobilization. LTB4APA and U75302, which are LTB4 receptor antagonists were given to C57BL/6 mice at different dose levels(0.5μg, 1μg, 2μg or PBS with equal volume in control arm) followed by rhG-CSF(5μg, IV) 2 hours later. 24 hours after the rhG-CSF injection, peripheral blood samples were obtained via cardiac puncture. The samples were analyzed for TNC using a trypan blue stain and FACS analysis were performed using Sca-1, Lin, CD45R(B220), CD116, Gr-1, TER119. The number of WBC and HSC were decreased in the rhG-CSF mobilized mice, in which LTB4 receptor antagonists were given. In those with up to 1μg of LTB4APA or U75302, there were tendencies of the blocking of the mobilization in the dose dependent manner. However, beyond 1μg of LTB4 receptor antagonists, the blocking effects plateaued. Interestingly, the blocking effects on mobilization by LTB4 receptor antagonists were more dramatic by the rh-GCSF than by the LTB4. Through our data, one can conclude that the LTB4 receptor is involved not only in the downstream pathway of rh-GCSF mobilization, but in the LTB4 mobilization pathway in C57BL/6 mice. Currently, hematopoietic stem cells mobilization is being tested to see the effects of rh-GCSF on LTB4 K/O mice. It is necessary to have insight into understandings more precise mechanisms on rhG-CSF and LTB4 mobilization for developing efficient protocols in the clinic.