bluuebunny/crossref_metadata_2025 huggingface dataset:
Lenalidomide/Dexamethasone Improves Response and Prolongs Time to Progression, Even in Patients with IgA Multiple Myeloma: A Sub-Analysis of the MM-009/010 Studies.
Authors: Foa Robert , Weber Donna , Dimopoulos Meletios , Olesnyckyj Marta , Yu Zhinuan , Zeldis Jerome , Knight Robert , Chanan-Khan Asher Alban
Published: October 2019

Background: Historically, patients with IgA multiple myeloma (MM) respond poorly to treatment. In 2 recent phase III trials, Lenalidomide (Len) in combination with Dexamethasone (Dex) led to an overall response (OR) rate of approximately 60% (61% in MM-009 and 60% in MM-010), a complete response (CR) rate of about 15% (14% and 16%, respectively), an overall survival (OS) of at least 29.5 months (29.5 and not yet reached), and a median time to progression (TTP) of at least 11.1 months (11.1 months and 11.3 months, respectively) in patients with relapsed/refractory MM. In both studies, OR, CR, OS and TTP were significantly better with Len/Dex than with Dex alone. Here, we assess the impact of IgA disease on the efficacy and tolerability of treatment with Len/Dex versus Dex alone.

Methods: Data were pooled from the MM-009 and MM-010 studies. Patients were randomized to receive Len (25 mg/day on days 1–21 of each 28-day cycle) or placebo. Both groups received Dex 40mg PO q.d. on days 1–4, 9–12, and 17–20 (for the first four cycles). After four cycles, Dex 40 mg/day was administered only on days 1–4. Response to therapy, TTP, OS, and adverse events were assessed. Response rate and TTP were based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]).

Results: Of 154 patients with IgA at baseline, 72 were treated with Len/Dex and 82 with Dex alone. Among those without IgA, 281 received Len/Dex and 269 received Dex alone. Baseline characteristics were balanced between treatment groups. Len/Dex was associated with a significantly higher OR and longer median TTP than Dex alone in patients with and without IgA (Table). In the non-IgA group, patients treated with Len/Dex had a significantly longer OS than those treated with Dex alone. Response, TTP and OS were comparable between IgA and non-IgA patient groups. There was no difference in the incidence of adverse events between patients with and without IgA. Among those with IgA, the most common grade 3–4 adverse events with Len/Dex and Dex alone were neutropenia (37.5% and 2.4%), thrombocytopenia (16.7% and 8.5%), and anemia (11.1% and 7.3%). The respective rates for patients without IgA were 46.5% and 14.5%, 12.1% and 5.7%, and 11.0% and 5.7%.

Conclusion: In patients with and in those without IgA MM, Len/Dex treatment induces a high response rate and a prolonged TTP compared with Dex.

IgA non-IgA Clinical response, % Len/Dex (n=72) Dex alone (n=82) P Len/Dex (n=281) Dex alone (n=269) P OR 68.1 18.3 <0.001 57.7 23.0 <0.001 CR 18.1 0 NS 14.2 2.6 NS PR 38.9 15.9 NS 35.6 19.3 NS Median TTP, wks 44.3 16.4 <0.001 52.1 20.1 <0.001 Median OS, wks 130.4 102.4 NS 156.0 136.1 <0.05
Varicella Zoster Virus Reactivation with the Use of Bortezomib in Relapsed or Refractory Multiple Myeloma Patients.
Authors: Kim Seok Jin , Lee Hyo-Jin , Kim Hawk , Kim Kihyun , Kwak Jae-Yong , Nam Seung-Hyun , Kwon Jung Hye , Sohn Sang Kyun , Won Jong-Ho , Lee Jae Hoon , Suh Cheolwon , Yoon Sung-Soo , Cha Yongjun , Kim Hye Jin , Kim Inho , Do Young-Rok , Lee Won-Sik , Joo Young-Don , Kim Hyo Jung ,   the Korean Multiple Myeloma Working Party (KMMWP)
Published: October 2019

Bortezomib has been used for patients with relapsed or refractory multiple myeloma. However, considering most patients with multiple myeloma are elderly people, the management of bortezomib-induced adverse effects became important. Varicella zoster virus (VZV) reactivation was reported as another adverse event associated with bortezomib in the APEX trial. Although some concomitantly administered drugs such as steroid may induce herpes zoster, proteasome inhibition itself may be associated with VZV reactivation because NF-κB inactivation may reduce antiviral response, and proteasome inhibition may affect the cellular localization of VZV leading to nuclear accumulation of VZV. Therefore, we analyzed the incidence of VZV reactivation among 267 relapsed or refractory myeloma patients treated with bortezomib. All patients were treated with at least one kind of treatment other than bortezomib before bortezomib therapy. 58 cases of VZV reactivation was observed (21.72%, 58/267) during or after bortezomib treatment while only 25 cases were found during other treatments such as VAD, MP etc (9.36%, 25/267). The incidence of VZV reactivation was not different based on the type of regimen: bortezomib monotherapy (22.58%) vs. bortezomib combined with dexamethasone, alkylating agents or thalidomide (22.72%). The characteristics of patients were compared in table.

VZV reactivation (−) VZV reactivation (+) P value † number of prior VZV/total number of patients, ‡median (range), mean ± SD Age (median, range) 63 (43–82) 63 (37–82) n. s. Gender (male: female) 129:80 32:26 n. s. Number of prior zoster† 20/209 5/58 n. s. Disease duration (mean± SD) 3.57±3.01 years 2.33±1.99 years < 0.05 Number of prior treatment‡ 3 (1–7), 2.68±1.29 3 (1–7), 2.57±1.22 n. s.

The incidence of VZV reactivation was not related with the disease (D-S stage, type), health status (performance status, co-morbidity, social history, blood cell counts), and other toxicity associated with bortezomib. The median time and mean cycles to the onset of VZV reactivation after the first infusion of bortezomib were 46 days (7–560 days), and 2.58±1.97 cycles. Localized herpes zoster was dominant form, and most cases showed a good response to anti-viral therapeutics without significant sequela. In conclusion, bortezomib was associated with high incidence of VZV reactivation. However, considering the absence of factors predicting VZV reactivation, further study should be warranted to determine the routine use of anti-viral prophylaxis.
Rapid Remission Induction by VTD (Velcade, Thalidomide, Dexamethason) in Patients with Multiple Myeloma and High Tumor Burden at Diagnosis.
Authors: Odelga Viktoria , Ackermann Jutta , Sagaster Verena , Kaufmann Hannes , Zielinski Christoph , Drach Johannes
Published: October 2019

Background: VTD was reported to be an active salvage regimen in patients with relapsed/refractory multiple myeloma (MM). Since initial results with VTD as frontline therapy were also promising, we used VTD as induction treatment prior to autologous transplantation in MM patients with particularly high tumor burden.

Methods: Velcade was administered at 1.3 mg/m2 on days 1, 4, 8, and 11; thalidomide was given as a daily dose of 100 mg; dexamethasone (20 mg per os) was given on days 1, 2, 4, 5, 8, 9, 11, and 12. Four cycles were scheduled every 3 weeks.

Results: We here report on three patients (age 36, 38, and 50 years) with newly diagnosed MM and high tumor mass at presentation (patient 1: Bence-Jones kappa MM with 95% plasma cell infiltration, serum free-kappa light-chains 4000 mg/l; patient 2: IgG-kappa MM with serum IgG > 9000 mg/dl, bulky plasmacytomas in the iliac bones; patient 3: IgA-lambda MM with 70% plasma cells in the bone marrow, IgA 4500 mg/dl, plasmacytoma in the os sacrum > 10 cm in diameter). Genetically, all 3 patients corresponded to the hyperdiploid variant (multiple trisomies, absence of del(13q14) and del(17p13)); patient 1 also had a t(11;14) and gain of chromosome 1q21. VTD resulted in a paraprotein reduction of at least 75% already after cycle 1. Rapid tumor mass reduction was not associated with signs of tumor lysis, and patient 1 had a significant improvement in renal function (serum creatinine from 2.4 to 1.3 mg/dl). After 4 cycles of VTD, patients 1 and 2 achieved a CR including a normal kappa/lambda ratio in the free-light-chain assay (patient 3 still ongoing). Patients have already completed G-CSF primed peripheral stem cell collection and autologous transplantation. Toxicity of VTD was mild (transient nausea and diarrhea in patient 2), in particular no peripheral neuropathy (grade 2 or higher). 7 additional pts are still at an early phase of VTD treatment, and data will be available at the meeting.

Conclusion: Induction treatment with VTD results in an effective tumor mass reduction already within one cycle and should be further evaluated in MM patients in need of rapid disease control.
(−)-Epigallocatechin-3-Gallate (EGCG), Green Tea Component, Antagonize the Anti-Myeloma Activity of Proteasome Inhibitor PS-341 by Direct Chemical Interaction.
Authors: Kim Tae Young , Park Jongmin , Oh Bora , Min Hyun Jung , Jeong Tae-Sook , Lee Jae Hoon , Park Seung Bum , Lee Dong Soon ,   the Korean Multiple Myeloma Working Party (KMMWP)
Published: October 2019

PS-341 (also known as bortezomib, Velcade®) has a remarkable anti-myeloma acitivity and is also potential candidate for the treatment of other tumors either alone or in combination with other chemotherapeutic agents. Investigations on the effectiveness of PS-341 in combination with other anti-neoplastic agents are currently under clinical trial. Since (−)-epigallocatechin-3-gallate (EGCG) has been reported its anti-cancer activity in various cancer types, we tried a co-treatment of PS-341 with EGCG on myeloma cells, expecting a synergistic effect. However, the anti-cancer activity of PS-341 was blocked by EGCG without any synergistic effect. At the early stage of our research, we suspected antioxidant function of EGCG is the main cause of antagonistic effect on PS-341-induced cell death. Thus we selected polyphenols showing strong antioxidant function including vitamin C. But, we did not obtain any consistant data that support the significant correlation of antioxidant function of polyphenols with antagonistic effects. Instead, the structural features of polyphenols showed striking correlations with antagonistic effect; especially the presence or absence of vicinal diol moiety on polyphenol was the key elements for the effective blocking on anti-cancer function of PS-341. We infer that vicinal diols on polyphenols interact with boronic acid of PS-341, which convert active triangular boronic acid (sp2 character) of PS-341 to inactive tetrahedral boronate (sp3 character) through direct chemical interaction. The equilibrium of this conversion is controlled by structures and concentration of polyphenols, and this conversion abolished the anti-myeloma activity of PS-341. We confirmed our hypothesis on direct chemical interaction of PS-341 with EGCG through 11B NMR experiment and cell viability assay data clearly support the antagonistic interaction between PS-341 and polyphenols in multiple myeloma cell lines and primary myeloma cells from patients. Based on our researches, restriction of the intake of natural polyphenols by food or vitamin supplements should be considered during the treatment with PS-341 in MM patients.

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Pure Hematopoietic Stem Cells Reconstitute Immunity in Allogeneic Hosts Superior to Bone Marrow: Immunosuppression by Subclinical Graft-Versus-Host Disease.
Authors: Tsao Gabriel J. , Allen Jessica A. , Logronio Kathryn , Lazzeroni Laura C. , Shizuru Judith A.
Published: October 2019

Antigen specific immune responses are known to be impaired following allogeneic hematopoietic cell transplantation (HCT). Some clinical studies suggest that graft T cell depletion for the prevention of graft-versus-host disease (GVHD) leads to poorer immune recovery, while other correlate GVHD with delayed immune reconstitution. Our studies sought to examine the degree to which the co-transplantation of GVHD-inducing mature cells mediated protective immunity post-HCT. We compared the transplant of FACS purified hematopoietic stem cells (HSC: cKit+Thy1.1loSca+Lin-) with bone marrow (BM) between congenic (BA to B6Ly5.2), minor-antigen mismatched (BA to BALB.B), haploidentical (BAxSWR F1 to BALB/cxSWR F1) and MHC-mismatched (BA to BALB/c) donor and host pairs. We show that grafts composed solely of purified HSC give uniformly superior lymphoid reconstitution across all mismatched pairs, both qualitatively and quantitatively. Although absolute blood lymphocytes counts were increased in recipients of BM compared to HSC, lymphoid reconstitution as measured by lymph node size, counts and architecture was significantly improved in the HSC groups regardless of minor or major mismatches between donor and host. Proliferative responses to the allele specific peptides of the antigen hen egg lysozyme were also significantly increased in the HSC as compared BM recipients (p=0.028), with fully MHC mismatched BM recipient cells showing almost no proliferative response. The use of MHC allele specific antigens also revealed that T cell responses post-HCT are dominated by donor-restricted elements. These data suggest that subclinical GVHD mediated by mature cells in the donor BM result in impaired immune reconstitution. While there may be an increase in absolute lymphocyte numbers, this increase does not correlate with an increase in immune cell function. These findings provide important insight into the benefits of purified HSC for preventing post-HCT infectious complication in addition to its known GVHD prophylaxis benefits. Our data highlights the benefit of transplanting a pure HSC population, as the relatively small number of T cells that are found in mouse bone marrow or that remain in the graft after T cell depletion in humans can still result in immune impairment due to subclinical GVHD.
IL-2- and IL-15-Activated Alloreactive NK Cells Infusion Reduces GVHD, Mediates Graft-Versus-Leukemia Effects and Prolongs Survival in Recipients of MHC-Mismatched Hematopoietic Cell Transplantation.
Authors: Chen Guanghua , Wu De Pei , Yang Mingzhen , Sun Ai-ning
Published: October 2019

Alloreactive NK cells with killer immunoglobulin-like receptor (KIR) ligand incompatibility have been implicated to reduce graft-vs-host disease (GVHD) and myeloid leukemia relapse in clinical hematopoietic cell transplantation (HCT). Murine NK cells express subgroups of H-2-specific receptors of the C-type lectin superfamily, termed Ly49, that regulate their function. IL-2 and IL-15 are two important NK cell growth cytokines. We investigated if IL-2- and IL-15-activated alloreactive NK cells would reduce GVHD and mediate graf-versus-leukemia effects in mice undergoing MHC-mismatched allogeneic HCT. 6–8-week-old female specific pathogen-free BALB/c mice were injected intravenously with 1×106 EL9611 erythroblastic leukemia via lateral tail vein. Eight days following leukemia inoculation, leumemia-bearing mice were irradiated (800cGy) with 6MV X—ray and transplanted with 5x106 bone-marrow cells and 10x106 splenocytes from MHC-mismatched C57BL/6 mice. One day following transplantation, recipient mice were given a single infusion of 1×107 IL-2- and IL-15-activated donor NK cells. Recipients of alloreactive NK cells had a significant reduced clinical GVHD scores(p<0.01), and prolonged survival (p<0.01) compared to HCT recipients not receiving alloreactive NK cells. These data provide an in vivo evidence that a single infusion of alloreactive NK cells can reduce GVHD and prolong leukemia-bearing mice survival via graft-versus-leukemia effects following MHC-mismatched allogeneic HCT.
Post Allogeneic Stem Cell Transplant Complications - Single Centre Experience from Pakistan.
Authors: Raza Shahid , Ullah Khalil , Ahmed Parvez , Satti Tariq , Khan Badshah
Published: October 2019

Over last five years 154 patients received HLA matched sibiling transplants at Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. Indications for transplant included Aplastic anemia, B-Thalassaemia major, Chronic Myeloid leukemia, Acute leukemias, and miscellaneous disorders which included Myelodysplastic syndrome, Fanconi’s anemia, Non-Hodgkin lymphoma, and Gaucher’s disease. All patients received standard conditioning regimens and GvHD prophylaxis. Pre-transplant infection surveillance was carried out in all patients and strict prophylaxis against infection was observed as per our transplant policy. During post transplant follow up we encountered certain infective and non infective complications. These included: acute GvHD (grade II–IV) 28.5%, chronic GvHD 15.5%, haemorrhagic cystitis 9.7%, VOD liver 5.1%, acute renal failure 3.2%, bacterial infections 51.2%, fungal infections 15.0%, CMV infection 4%, herpes zoster 4%, tuberculosis 2.6%, pneumocytitis jiroveci infection 0.6%, malaria 0.6% patient, graft rejection 5.2% patients and relapse in 4%patients. We encountered certain rare unexpected post transplant complications which have been rarely reported in literature before. These included Hickman catheter embolization, Guillain Barre syndrome, co-infection with pneumocystis jirovicii and a rare fungus trichosporon beigilii, cyclosporine induced uncontrolled seizures, idiopathic polycythemia, haemorrhagic pericardial effusion with cardiac temponade, deep vein thrombosis, dengue fever and measles. These complications were effectively managed in our centre. There was only one death associated with these complications. Mortality was observed in 27.2% patients. Mortality related to non-infective complications was 14.2%. Major non-infective causes of mortality were GvHD, VOD, disease relapse, intracranial haemorrhage and acute renal failure. Mortality related to infections was 13%. Fatal infections included CMV disease, disseminated aspergillosis, pseudomonas septicaemia and tuberculosis.
Mesenchymal Stem Cells for Treatment of Refractory Chronic Graft-Versus-Host Disease.
Authors: Jianyu Weng , Du Xin , Peng Xiang , Xiumin Zhang , Wu Suijin , Lu Zesheng , Luo Chengwei , Guo Rong , Deng Chengxin , Ling Wei , Lin Wei , Huang Zilun
Published: October 2019

Refractory extensive chronic graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation (SCT) is associated with high mortality [Margolis J., SeminOncol 2000].However, conventional therapies including steroids are often unsuccessful in those patients with multiorgan involvement and are associated with significant therapy-related complications and poorly life quality. Mesenchymal stem cells (MSCs) have immunomodulatory effects [Tse WT et al., Transplantation 2003; Spees JI et al.,Proc Natl Acad Sci USA 2003]. Recently MSCs have been given intravenously to treat seven steroid resistant acute GVHD patients and one patient with chronic GVHD. MSCs effects in chronic GVHD is rarely known, although this successfully experience suggests that MSCs have been well tolerated and had a powerful immunosuppressive effects on acute GVHD. [Katarina Le Blanc et al., Lancet 2004; Olle Ringden., Transplantation 2006 ]. Here, we present our experience of using MSCs for treatment of Thirteen patients with refractory chronic GVHD. Between May 2005 and March 2007, thirteen patients (8 male, 5female) with hematological malignancies with a median age of 26(range:15 to 40) years who had received peripheral stem cells from sibling donors. All patients developed steroid resistant or extensive chronic GVHD, with progressive involvement of the skin(13), liver(10), oral mucosa(12),ocular glands(12), and thrombocytopenia (1) when the immunosuppressive agents were taped after five to twenty-four months. The MSC dose was median 1.0 ×106 cells/kg body weight of the recipient. In all, thirteen patients had at least received one dose, seven patients received more than two doses. MSC donors were in seven cases HLA-identical siblings, six unrelated mismatched donors. No side-effects were seen after MSCs infusions. All patients have responded after follow-up of the median time 15 months. One patient with moderate cGVHD had a complete responses, and discontinued all of the immunosuppressive agents without relapse more than 18.4 months after MSC infusion. Three moderate and two patients with severe chronic GVHD improved to mild degree, and six severe turned to moderate degree. Complete resolution was seen in gut(2/3), liver(5/10), skin(5/13), oral(6/12) and eye(2/12). One patient responded in skin, liver, oral mucose and eye, but developed in lung (bronchiolitis obliterans, BO) score of 2 which are considered severe chronic GVHD. Mean follow-up periods was 27m (rang: 14 to48m), Leukemia free survival(LFS)rate were 85%(11/13), and the overall survival (OS)rate were 92.3%(12/13). Our experience suggests that MSC infusion is a safe and effective adjunct therapy for refractory extensive chronic GVHD with resistance to conventional therapy. But more prospective, controlled studies with MSCs for treatment of GVHD should be performanced to evaluate this new treatment exactly.
Treatment of Intractable Graft-Versus-Host Disease with Bone Marrow Derived Mesenchymal Stem Cells - A Pilot Clinical Trial.
Authors: Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Seol Miee , Lee Young-Shin , Ryu Seong-Gil , Kang Young-Ah , Lee Kyoo-Hyung
Published: October 2019

Recent studies have shown that mesenchymal stem cells (MSCs) have profound immunomodulatory function, both in vitro and in vivo. There are several reports to treat effectively therapy-resistant graft-versus-host disease (GVHD) using ex vivo expanded MSCs. We performed a pilot clinical trial to treat intractable GVHD with bone marrow derived MSCs. All of 5 patients, 3 males and 2 females, with steroid-refractory GVHD were included in this study. Age range was 27 to 48 years old. Diagnosis of underlying disease was CML in 2, AML in 1, ALL in 1, and MDS in 1. Hematopoietic stem cell (HSC) donor was a sibling in 2 and an unrelated volunteer in 3. The donor of MSCs was a sibling in all patients: two donors were the same to HSC donors, but other three were not. About 20 mL of bone marrow was aspirated from donors and MSCs were cultured ex vivo. After about 3 weeks, MSCs were harvested for the first infusion, and 4 more weeks’ culture was done for the planned second infusion. The infused doses of MSCs were 5.3 to 6.9 x 106/kg for the first infusion and 1.8 to 7.0 x 106/kg for the second infusion. The onset of GVHD was post-transplant day 24 to 191 and the times from the onset of GVHD to the infusion of MSCs were 73 to 2469 days. There were no adverse events related to the infusion of MSCs. Three patients did not show any response to the treatment of MSCs for GVHD and two showed minimal response: transient improvement of jaundice and diarrhea without improvement of skin GVHD lesions in one patient, and improvement of performance status without significant increase of pulmonary function test parameters in another patient with lung involvement of GVHD. There were no significant changes in hemoglobin, and peripheral blood counts of platelets, leukocytes, lymphocytes, CD3+ cells, CD4+ cells, CD8+ cells, NK cells and B cells over 6 months’ period after the infusion of MSCs. Results of our pilot study suggest that the treatment effects of MSCs may be limited in patients with chronic established GVHD. Further studies on MSCs for GVHD should be focused on acute or exacerbated GVHD.
Chronic Graft-Versus-Host Disease after Tacrolimus Versus Cyclosporine for Graft-Versus-Host Disease Prophylaxis in Pediatric Patients Undergoing Matched Unrelated Donor Hematopoietic Stem Cell Transplantation. A Pediatric Blood and Marrow Transplant Consortium Study..
Authors: Atlas Mark P. , Yanik Greg , Schultz Kirk R. , Goyal Rakesh K.
Published: October 2019

Chronic graft versus host disease (GVHD) is a significant cause of morbidity and mortality in matched unrelated donor hematopoietic stem cell transplantation. Incidence of acute GVHD is a major risk factor for chronic GVHD. Calcineurin inhibitors form the backbone of graft versus host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation. When comparing cyclosporine to tacrolimus for GVHD prophylaxis, we previously reported a trend toward superiority of cyclosporine as prophylaxis against acute GVHD. We now analyze their effect on the incidence and severity of chronic GVHD. In a multi-institutional trial, we prospectively collected the clinical data on 141 evaluable patients receiving either cyclosporine/methotrexate or tacrolimus/methotrexate based prophylactic regimens for 6/6 matched unrelated donor, transplant. Conditioning regimens were fully ablative; no T-cell depletion was permitted; cord blood donors were excluded. Patients were required to receive either cyclosporine or tacrolimus, but the choice was per investigator preference. The two arms were reasonably balanced: 60.1% of patients received cyclosporine and 39.9% of patients received tacrolimus. Rates for acute GVHD were 60.4% for cyclosporine and 73.8% for tacrolimus (p = 0.086). Rates for chronic GVHD were 44.2% for cyclosporine and 47.3% for tacrolimus (p = 0.7). In the 61 patients with chronic GVHD, extensive disease was present in 82.9% of cyclosporine group and 80.8% of the tacrolimus group (p = 1.0) Those graded as moderate or severe comprised 80% of the cyclosporine group and 56% of the tacrolimus group (p = 0.46) and those both extensive and moderate or severe were 71.4% and 52%, respectively (p = 0.12). In pediatric matched unrelated donor transplantation, the incidence and severity of chronic graft versus host disease in patients receiving either tacrolimus/methotrexate or cyclosporine/methotrexate based regimens for prophylaxis of GVHD are not significantly different.
Adapting Cyclosporine to Calcineurin Activity Rather Than to Cyclosporine Blood Levels: Toward a Functional Management of Graft-Versus-Host Disease Prophylaxis.
Authors: Sanquer Sylvia , Maury Sebastien , Hicheri Yosr , Martin Elvira , Robin Marie , Pautas Cecile , Barouki Robert , Socie Gerard , Kuentz Mathieu , Cordonnier Catherine
Published: October 2019

We have previously shown [1] that a calcineurin activity (CA) < 28 pmol RII/mg proteins/min was significantly associated with the absence of acute GVHD after allogeneic stem cell transplant (SCT). The CA is poorly correlated with cyclosporine (CsA) trough level which is not a good marker of CsA efficacy. Therefore, the in vitro assessment of CA could help in adapting the cyclosporine doses for GVHD prophylaxis, better than blood CsA levels. Objective: The aim of this prospective study was to evaluate the feasibility of adapting the CsA doses to the values of in vitro CA either until GVHD occurs, or until day 100, whichever occurs first.

Methods: CA assessment methods in PBMC of transplant patients and monoclonal CsA level measurement methods were previously reported [1]. CA and CsA levels were measured once a week from d0–d15, twice a week from d16–d35, then once a week up to d100. The CsA doses were adapted in order to maintain a CA < 28 from transplant by 20% progressive changes of the CsA daily dose. Adaptation was stopped in case of clinical CsA blood levels ≥ 600 ng/ml, creatinine clearance < 40 ml/mn, serum bilirubin > 40 m/L, or severe clinical toxicity.

Patients: 39 adult patients with malignant hemotologic diseases (acute leukemia: 28; chronic leukemia: 4; others: 4) or aplastic anemia (3), and undergoing myeloablative SCT were included (HLA-id donor: 20; unrelated donor: 19). GVHD prophylaxis consisted in short course Methotrexate and CsA (initial dose: 3 mg/kg IV).

Results: Out of 39 patients, 2 were adapted until d100 and did not develop GVHD; 27 were adapted without CsA toxicity until they developed GVHD (grade I: n=2; grade II: n=18; grade III–IV: n=7). In 10 (26%) patients, adaptation was stopped before d100, due to neurologic (n=1), renal (n=2) or liver (n=2) toxicity, severe nausea (n=1), investigator decision (n=1) or protocol violation (no CsA increase despite high CA and no CsA toxicity: n=3).

Conclusion: Our study shows that CsA dose adaptation is feasible on the basis of CA regular assessment within the safety limits defined in our protocole. This adaptation is, however, limited by CsA toxicity, due to the need to significantly increase the CsA dose to get a CA < 28 pmol in 26% of the patients. A prospective controlled study is needed to compare the routine use of CA to the use of CsA blood levels for managing CsA doses in GVHD prophylaxis.
Efficacy and Safety of Early Administration of Mycophenolate Mofetil to Steroid-Resistant Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation: A Single Institution Study.
Authors: Mori Masaki , Muroi Kazuo , Matsuyama Tomohiro , Oka Satoko , Yamamoto Chizuru , Ozawa Keiya
Published: October 2019

Introduction: Acute graft-versus-host disease (aGVHD) remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT), and is associated with significant morbidity and mortality. Mycophenolate mofetil (MMF) has been known as a key drug, with which aGVHD and chronic GVHD are treated in Western countries, but it remains unclear when and how MMF is administered to GVHD in Japan. We evaluated the efficacy of treatment with MMF to steroid-resistant aGVHD.

Patients and Methods: For eligibility, thirteen patients were ten men and three women after eighty-eight HSCT in our center from 2001 to 2007, retrospectively. Among them, 6 acute myelogenous leukemia, 2 acute lymphoblastic leukemia, 2 chronic myelogenous leukemia, 2 lymphoblastic lymphoma, and 1 adult T-cell leukemia were diagnosed. Four peripheral bloods, 8 bone marrows and 1 cord blood were transplanted from 2 mothers, 4 siblings and 7 unrelated donors with the conditioning treatments, including 9 total-body irradiation-based regimen, 2 busulfan plus cyclophosphamide and 2 reduced-intensity regimen. The numbers of HLA-mismatch locus were serologically one at 4/6, four at 5/6, and genetically one at 2/6, three at 4/6 and three at 5/6. GVHD prophylaxis included FK506 plus methotrexate (MTX) and/or antithymocyte globulin for 9 patients, and cyclosporine and MTX for 4 patients. Steroid at a dose of 1∼2 mg/kg per day firstly was administered for the treatment of aGVHD of grade II to IV. Then, all of refractory or steroid-tapering-failure cases were treated with the second-line MMF as the steroid-refractory aGVHD, including methylprednisolone pulse therapy in eight.

Results: Max doses of MMF at 1g of three patients, 2g of nine patients and 3g of one patient were required in our cases, but less than in Western countries as reported. Onsets of MMF starting day were from 27 days to 139 days after HSCT, and less than 53 days among them except for one. Target organs were skin (more than stage 3) in seven, skin+gastrointestinal tracts (GI) in four, and skin+GI+liver in two. Acute GVHD grades were II–IV in all and III–IV in six, even though 12 patients were improved and successfully tapered the amounts of steroid. The adverse events were diagnosed as cytopenia in 2 patients (15%) and infectious events in 7 patients (54%) including CMV antigenemia in 5 patients, though were tolerable to all patients except for one, which discontinued MMF due to grade 3 neutropenia. GI tract disorder was not complicated in all patients. As a consequence, relapse mortality was 31% (4/13), but non-relapse mortality was zero percent.

Conclusion: We consider that MMF is more beneficial and well tolerated for the treatment of steroid-refractory aGVHD, and the early administration of MMF as a second-line therapy is more important.
Chronic Graft Versus Host Disease and Pretransplant Disease Status Predict Outcomes in Patients with Hematologic Malignancies Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation.
Authors: Shah Megha A. , Agha Mounzer , Mapara Markus , Lenhart Kate , Raptis Anastasios
Published: October 2019

Reduced intensity stem cell transplantation (SCT) is an effective treatment modality for patients with hematologic malignancies who are not candidates for conventional myeloablative SCT. We conducted a retrospective review of all patients with hematologic malignancies receiving a reduced intensity allogeneic SCT from July 2002 to July 2007. Data pertaining to patient demographics, engraftment, disease status pre and post transplant, graft versus host disease (GVHD), and HLA matching was analyzed to identify factors significantly affecting the clinical outcome. Seventy three patients, with a median age of 55 (range of 19–70) and with the diagnoses of ALL (n=8), AML (n=30), CLL (n=3), CML (n=1), Hodgkin’s (n=7), non-Hodgkin’s (n=7), MDS (n=11), and MM (n=6) underwent a reduced intensity SCT using a fludarabine based conditioning regimen. Thirty nine (53%) received unrelated donor grafts and 34 (47%) received sibling donor grafts. Fifty six patients (77%) received fully matched grafts whereas 17 patients (23%) had an antigen or allele mismatch. Acute GVHD grade II-IV was observed in 27 of the 73 patients and chronic GVHD was seen in 18 of the 48 patients who could be evaluated. Seventeen patients developed transplant related fatal complications and 30 patients died from disease progression or relapse. Median time to neutrophil recovery was 15 days (range of 9–41 days) and median time to platelet recovery was 18 days (range of 9–42 days). Graft failure was observed in 6 of the 73 patients. Median overall survival and disease free survival for all patients was 7.7 and 6.6 months respectively. Median overall survival for patients with persistent disease or in remission at the time of the SCT was 5.6 and 21.8 months (p= 0.01) while that for disease free survival was 5.7 and 8.4 months (p=0.06). Median overall survival with and without chronic GVHD was 25.6 and 9.4 months (p <0.0001) while median disease free survival was 18.2 and 6.0 months (p< 0.0001). Patients with limited chronic GVHD have not yet reached median overall survival while the median disease free survival was 18.4 months. Those with no or extensive chronic GVHD had medians of 9.4 and 9.2 months for overall survival and 6.0 and 9.2 months for disease free survival (p= 0.004 and p=0.02). The source of the stem cells as well as the administration of allele or single antigen mismatch grafts did not affect the outcome. Reduced intensity SCT is an effective treatment modality in patients with hematologic malignancies, though it is most effective in patients who are in remission at the time of transplant and should be offered in this setting. Patients with limited chronic GVHD had a better outcome suggesting the presence of potent anti-tumor activity of the donor immune competent cells without the detrimental effects in clinical outcome caused by extensive chronic GVHD.
Germinal Center Phenotype Determined by Immunohistochemistry on Tissue Microarray Does Not Correlate with Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with Immunochemotherapy in the Randomized Trial LNH98-5. A GELA Study.
Authors: Molina Thierry Jo , Gaulard Philippe , Jais Jean-Philippe , Salles Gilles Andre , Berger Françoise , Haioun Corinne , Tilly Herve , Emile Jean-François , Feugier Pierre , Leroy Karen , Briere Josette , Coiffier Bertrand
Published: October 2019

Germinal center (GC) subtype defined by immunohistochemistry in diffuse large B-cell lymphoma (DLBCL) treated by anthracycline-containing regimens has been found as a good prognostic parameter by some but not all authors. More recently, studies reporting series of patients treated with rituximab plus chemotherapy showed a loss of prognostic value of GC profile. However, these series did not include patients from randomized trials. We undertook an immunohistochemical study on tissue microarray (TMA) among patients included in the GELA LNH98-5 trial that compared CHOP and rituximab-CHOP (R-CHOP). Among the 399 patients (age 60 to 80 years) enrolled in this study with DLBCL, duplicate TMAs were available for 172 patients, consisting for each TMA of two cores of 0.6mm per case. We analyzed the expression of CD10, bcl-6 and mum-1 and classified patients as GC or non-GC (n-GC) according to the Hans’ algorithm. The samples were scored positive for bcl-6 and mum-1 if 30% or more of tumor cells were stained and for CD10 if there was a significant number of tumor cells positive. Internal controls for each spot were required for interpretation as well as concordance between the duplicate TMAs. T-cell-rich B-cell lymphomas (TCRBCL) were excluded because too few tumor cells could be evaluated. Overall 101 patients were evaluable (excluding 39 cases due to absence of internal controls or spots detachment, 25 discordant cases between the duplicates for bcl-6 and mum-1, and 7 TCRBCL). Patient characteristics were not statistically different from the whole series regarding sex, age, stage, LDH level, PS, number of extranodal sites, aa-IPI, IPI, median follow-up (85 months) as well as allocated regimens (CHOP, 49 patients; R-CHOP, 52 patients). 44 patients were classified as GC and 57 as n-GC. Patient characteristics were well balanced between GC and n-GC subtypes. EFS was not different among the 101 patients between GC and n-GC (p=0.28). Multivariate analyses confirmed that only aa-IPI (p=0.005), and treatment arm (p=0.005) influence EFS but not the GC/n-GC profile (p=0.17). Although the EFS among CHOP patients showed a borderline but not significant better prognosis among GC patients (p=0.11), this trend was completely abrogated among patients treated with R-CHOP (p =0.92). Overall survival was not different between the GC and n-GC profile among the whole population (p=0.41), the patients treated by CHOP (p=0.31) or by R-CHOP (p=0.74). Overall, our study demonstrates that in this randomized trial, GC profile defined by immunohistochemistry on TMA does not represent a significant prognostic parameter among DLBCL patients treated by CHOP with or without rituximab.
Age under 40 Does Not Confer Superior Prognosis in Patients with Multiple Myeloma Undergoing Upfront Autologous Stem Cell Transplant Despite High Response Rates.
Authors: Cheema Parneet K. , Zadeh Sahar , Reece Donna , Chen Christine I. , Trudel Suzanne , Kukreti Vishal , Mikhael Joseph R.
Published: October 2019

BACKGROUND: Multiple myeloma (MM) only occurs in 2% of patients under the age of 40. It has been reported that this young cohort of patients have a superior overall survival when compared to those over the age of 40.

OBJECTIVE: To evaluate the clinical and laboratory features of patients ≤40 years of age at diagnosis of MM and to compare survival outcomes to patients >40 years of age.

METHODS: Retrospective institutional review of all patients ≤40 years of age at time of diagnosis of MM that had underwent upfront ASCT at PMH from January 1, 1990 to July 31, 2007. Outcomes were compared to patients >40 years of age who had also undergone ASCT as upfront therapy.

RESULTS: 37 patients ≤40 years of age were identified. Twenty patients were male. Immunoglobulin subtype was as follows: 49% had IgG, 19% light chain,16% IgA, 8% IgD, and 5% IgG plasma cell leukemia. The main presenting clinical feature was bone pain (63%). 73% had radiological evidence of bony disease at diagnosis and 53% of these patients required radiation prior to ASCT. Clinical features included anemia in 81%, renal insufficiency in 39% and hypercalcemia in 28%. Conditioning regimens for ASCT were high dose melphalan (200mg/m2) alone in 25 pts, VP-16 & melphalan +/− TBI in 8 pts, bleomycin & cyclophosphamide in 3 pts, and in 1 pt it was unknown. Median time to engraftment of neutrophils (>0.5 x 109/L) and platelets (>20 x 109/L) was 11 days (range 8–18) and 12 days (range 0–54), respectively. Median duration of hospitalization was 17 days (range 10–54). No treatment related mortality was experienced. Response to ASCT was as follows in 29 evaluable pts: CR in 10 (34.5%), PR in 13 (44.8%), MR in 1 (3.4%), SD in 3 (10.3%), and PD in 2 (6.9%). Five patients underwent a tandem ASCT. Maintenance therapy was instituted in 11 pts. Median progression free survival (PFS) post ASCT was 23.0 months, which is similar to the PFS of 28.5 months in patients over 40 (p=0.559). There was also no difference in median overall survival (OS) from date of ASCT between the two groups (6.6 years in pts ≤40, 6.7 years in pts >40; p=0.797).

CONCLUSION: Young patients with MM present with advanced disease as evidenced by anemia, bone involvement and hypercalcemia. ASCT yields high response rates, but PFS post ASCT is less than 2 years. Although young age has been historically been considered to be a positive prognostic marker, OS post ASCT is only 6.6 years, which is equivalent to those >40 years of age. Strategies to better the outcomes of young patients with MM are required.
Clinical Characteristics of Patients with a RBC Fragment Flag on the Advia® 2120 Automated Hematology Analyzer.
Authors: Ben-Ezra Jonathan
Published: October 2019

The clinical diagnosis of thrombotic thrombocytopenia purpura (TTP) is a difficult one to make. It is based on clinical criteria, one of which is a microangiopathic hemolytic anemia, characterized morphologically by the presence of schistocytes on the peripheral blood smear. The ADVIA 2120 automated hematology analyzer is able to quantify the presence of red blood cell (RBC) fragments. We studied the ability of the ADVIA 2120 to be able to detect RBC fragments in the blood of TTP patients, and the characteristics of all patients in whom RBC fragments were obtained. During the study period, 6 TTP patients were studied. The initial numbers of RBC fragments ranged from 0.02–0.05 × 106 cells/μl. During the course of plasmapheresis, these numbers decreased to 0.00–0.02 × 106 cells/μl, corresponding to a rise in the platelet count.

Figure Figure In the course of a month, 52 blood samples on 39 patients were flagged by the hematology analyzer to have RBC fragments (0.01–0.12 × 106 cells/μl).

52 Samples with RBC Fragment Flag Hemoglobin Platelets RDW Range 4– 14.3 g/dl 5–906 × 103/ul 13.9– 28.6% Number Abnormal 46 (<13.0 g/dl) 23 (<160 × 103/ul) 51 (>14.1%)

Within this population, there were two patients with TTP, and one with DIC. Four of the samples did not have detectable schistocytes upon visual inspection of the peripheral blood smear. There were 19 samples from 14 patients who had RBC fragment counts ≥ 0.04 × 106 cells/μl.

19 Specimens with RBC Fragments ≥ 0.04 × 106/ul Hemoglobin Platelets RDW Range 8– 14.1 g/dl 59– 906 × 103/ul 16.4– 25.3% Number Abnormal 15 (<13 g/dl) 4 (<160 × 103/ul) 19 (>14.1%)

The diagnoses in these 14 patients were iron deficiency anemia (4 patients), thalassemia trait (2), acute lymphoblastic leukemia (2), and one each with TTP, sickle cell anemia, heart failure, kidney stone, cerebrovascular accident (CVA), and end stage renal disease. We conclude that the RBC fragment flag on the ADVIA 2120 is nonspecific. Although it does detect schistocytes in TTP, these are often present in low numbers. Quantitatively, the most numerous RBC fragments are found in diseases with marked anisopoikilocytosis, such as iron deficiency anemia.
Osteonecrosis of the Jaw Related to Bisphosphonates Therapy in Multiple Myeloma and Metastatic Prostate Cancer Patients. A Latin American Report: An Adverse Event To Look For!!.
Authors: Beltran Brady , Riva Luis , del Carpio Daniel , Fernandez Ivan , Vera Luis , Reategui Rocio , de Mendoza Fernando Hurtado , Castillo Jorge , Carrasco-Yalan Antonio A.
Published: October 2019

Background: Association between osteonecrosis of the jaw (ONJ) and aminobisphosphonate treatment in patients (pts.) with multiple myeloma, breast cancer and prostate cancer has been increasingly reported in the literature. Risk factors for this complication include presence of infection, recent dental extraction and any oral surgical procedure with bone exposure.

Patients and Methods: All patients with myeloma multiple or prostate cancer diagnosis treated at two institutions from Lima with either IV zoledronic acid or pamidronate from 2005–2007 were evaluated using outpatient records. Patients with ONJ were identified and their characteristics were compared to all patients receiving bisphosphonate therapy.

Results: One hundred eighty three patients were evaluated. One hundred three had metastatic prostate cancer, and eighty myeloma multiple. All patients with myeloma multiple received pamidronate and all patients with prostate cancer received zoledronic acid. Six patients developed ONJ (3.2%). Five pts. were male and one female; a median age of 62 (range 50–74) and 5 had metastatic prostate cancer and 1 myeloma multiple. Zoledronic acid and pamidronate were involved in 5 and 1 cases respectively. The median number of bisphosphonate infusions prior to the development of ONJ was 16 (range 12–20). No patient had dental extraction or oral surgical procedure before ONJ. Bone exposition occurred in four cases. Treatment was antibiotics in all cases and surgery in two.

Conclusions: ONJ is a serious complication of bisphosphonate therapy and it affected a significant proportion of our Latino american patients.
Imatinib Versus Interferon-alpha (IFN) for Patients with Newly Diagnosed Chronic-Phase (CP) Chronic Myeloid Leukemia (CML) from the Chinese Public Healthcare System Perspective: 12 Months Cost and Cost Per Responder Analyses.
Authors: Wang Chun , Chen Zi , Feng Weiwei
Published: October 2019

Background: Imatinib, a break-through oral molecular targeted therapy, has demonstrated impressive and durable responses as well as survival advantage over IFN based therapy in CML (1, 2). Reed et al. estimated the survival for a newly diagnosed CP CML patient treated with imatinib was 19.07 years vs. 9.09 years with IFN plus low dose cytarabine (LDAC) (3). However, imatinib has not been registered on the Chinese National Reimbursement Drug List (RDL) whereas IFN has. Although studies have shown IFN plus Ara-C is more effective than IFN alone, IFN is normally used alone in China in CP CML. Therefore, this study compared imatinib with IFN alone. Complete cytogenetic response (CCyR) at 12 months has been established as an effective measure for treatment efficacy in CML (4). The 12 months cost and cost per responder in CCyR analyses were conducted to compare imatinib with IFN alone from the Chinese public healthcare systems perspective.

Methods: The cost per responder at 12 months for a newly diagnosed CP CML patient was calculated as dividing the total 1-year cost of treatment by the CCyR rate at 12 months. The 1-year cost of treatment consists of the following occurred during one year: drug cost, office visits, and blood tests. The cost of managing adverse events was excluded as local China data were unavailable at the time of the analyses. The CCyR at 12 months for imatinib was obtained from the International Randomized Infereron vs. STI571 Study (IRIS) (1). The CCyR at 12 months for IFN was from the Baccarani et al. study (6). Price information on drugs was obtained from the listed retail price in China. The price for imported IFN was used as the cytogenetic response data were unavailable for domestic made IFN. Unit cost on office visit and blood test was estimated based on the average fees charged by tier 3 hospitals. Dosages for imatinib and IFN were based on the approved product labels in China.

Results: The 12-month CCyR rate for imatinib was 69% vs. 3% for IFN. The 1-year cost of treatment associated with imatinib was RMB77,700, lower than that with IFN (RMB79,200). The cost to achieve 1 CCyR at 12 month was RMB112,609 with imatinib vs. RMB2,640,000 with IFN.

Conclusion: In newly diagnosed CP CML, patients treated with imatinib achieved a significantly higher CCyR at a lower cost than those treated with IFN at 12 months. Based on the 1 year analysis, imatinib is a dominant treatment option in comparison to IFN in newly diagnosed CP CML treatment from the Chinese public healthcare system’s perspective.