Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on the health condition of cured adults ...are available whereas pediatric data cannot be transferred. The GMALL analyzed the health status in survivors of adult ALL retrospectively. Physicians answered a questionnaire on general condition (Eastern Cooperative Oncology Group ECOG status) and comorbidity or syndrome occurrence observed after treatment. Five hundred and thirty-eight patients with a median age of 29 (range, 15-64) years at diagnosis were analyzed, median follow-up was 7 (range, 3-24) years. Thirty-one percent had received SCT. ECOG status was 0-1 in 94%, 34% had not developed significant comorbidities. Most frequent comorbidities involved the neurologic system (27%), endocrine system (20%), skin (18%), graft-versus-host-disease (15%), cardiac system (13%), fatigue (13%). SCT impacted ECOG status and comorbidity occurrence significantly. ECOG 0-1 was observed in 86% of SCT and 98% of non-SCT patients (P<0.0001); comorbidity was observed in 87% and 57% respectively (P<0.0001). Our analysis elucidates the spectrum of comorbidities in cured adult ALL patients, with higher risk for transplanted patients, providing stimulations for the design of adequate aftercare programs. Overall, a large proportion of non-SCT patients achieved unrestricted general condition. The data provide a reference for new patient-centered endpoints in future trials.
Objective
Multidrug‐resistant organisms (MDRO) are a challenge in allogeneic hematopoietic cell transplantation (HCT). However, in the literature there is no comprehensive analysis on MDRO in HCT. In ...this retrospective, single‐center analysis, we appraised prevalence and clinical impact of MDRO in 98 consecutive allogeneic HCT patients.
Method
Prior to the conditioning (baseline) and whenever clinically indicated patients underwent a full screening for MDRO (stool and urine cultures, swabs from several body regions).
Results
It turned out that 26 patients were colonized by 33 MDRO, either at baseline (n=16) or at any other time until day 100 post‐transplantation. Of these 26 patients, eight developed an infection with MDRO, four of them by 4MRGN Pseudomonas aeruginosa, and three of them died MDRO‐related. However, there was no significant difference between MDRO‐colonized and non‐colonized patients regarding overall survival (OS) and non‐relapse‐mortality (NRM). There was only a trend toward a higher NRM in patients already colonized by MDRO at baseline. This was due to the high NRM in multidrug‐resistant P. aeruginosa‐colonized patients.
Conclusion
In summary, colonization with MDRO other than P. aeruginosa had no negative impact on NRM and OS. Patients colonized by multidrug‐resistant P. aeruginosa had a dismal outcome. HCT of these patients should be considered with care. Screening for MDRO in the pretransplant work‐up is suggested.
Purpose
Support groups might help survivors of allogeneic hematopoietic cell transplantations (HCT) to cope with medical, psychological, and social challenges. The aim of this project was (1) to ...establish a facilitated post-HCT support group and (2) to assess the participation behaviour.
Methods
From 11/2013 until 7/2017, all adult patients who had received a HCT at our centre were invited to participate in a professionally facilitated support group. The format of the group was unstructured without any rules regarding regular attendance. The attendance was prospectively minuted by the facilitator. Reasons for non-attendance were assessed by a survey.
Results
During the observation period, 53 group meetings were scheduled. Nine meetings were cancelled because of low attendance. Altogether 23 different patients (F:
n
=10; M:
n
=13) and 10 spouses (F:
n
=9; M:
n
=1) participated. Median participation was 5 range 2–11. With respect to all HCT patients who had the theoretical opportunity to attend, the mean participation rate was 7%. Thirteen patients and four spouses attended more than one meeting. The median count of participations among those participants was 8 2-32. The median interval from the first until the last participation was 16 months. The main reason reported for non-participation was the effort to get to the venue of the support group.
Conclusions
To our knowledge, this is the first analysis on the attendance behaviour of the participants of a support group for HCT survivors. The results provide guidance for the organization of future support groups and indicate what participation rates can be expected and how they might be increased.
Central venous catheters (CVC) placed either via the internal jugular vein (IJV) or the subclavian vein (SCV) are routinely used in patients with hematologic malignancies. In this retrospective ...study, we systematically compared CVC‐associated complications for both insertion sites, IJV and SCV. Between January 2011 and June 2013, all consecutive patients (n = 87) were included with at least one CVC (n = 153; n = 94 IJV; n = 59 SCV) at our institution due to induction/consolidation for AML/ALL or autologous hematopoietic cell transplantation (HCT). Primary study endpoints were central line‐associated (CLABSI), catheter‐related (CRBSI) blood stream infections and local inflammation (LI) at the insertion site. CRBSI occurred earlier and more frequently in the IJV‐ versus the SCV‐group with an incidence rate of CRBSI at day 15 of 10% versus 0% (p = .04) and a rate of CRBSI per 1000 CVC days of 5.7 versus 1.2. In addition, CLABSI was detected more often in IJV‐ compared to SCV‐CVC (26% vs. 8%, p = .009). Conversely, LI occurred more frequently and earlier in SCV‐ versus IJV‐CVC (88% vs. 56%, p < .0001) with a median time to LI of 9 versus 14 days (p < .0001). The strongest risk factor for the endpoints CRBSI, CLABSI, and LI was the insertion site. However, SCV insertion was a risk factor for LI (p = .001, HR: 2.0), insertion in the IJV a risk factor for CLABSI (p = .044, HR: 2.7) and CRBSI (p = .036, HR: 5.4). These results demonstrate a differential effect of the insertion site of CVC in neutropenic patients with a significantly reduced frequency of CVC‐related blood stream infections in SCV‐CVC.
Introduction: Major ABO-incompatible allogeneic hematopoietic stem cell transplantation (allo-HCT) is a common practice and represents a challenging transfusion scenario. Prolonged thrombocytopenia ...with increased platelet transfusion needs is one of its reported adverse effects, and this has been linked to the persistence of recipient anti-donor isoagglutinins. Case Presentation: A 55-year-old male patient, O Rh(D)-positive, with chronic myelomonocytic leukemia underwent major incompatible allo-HCT from a A Rh(D)-negative donor. He presented with prolonged thrombocytopenia and multiple transfusion reactions after A Rh(D)-negative platelet transfusions. Considering the outcomes of numerous examinations, we tested the anti-A1 titers, finding a significant persistence of anti-donor isoagglutinins. We limited platelet transfusions to blood group O Rh(D)-negative donors, which significantly decreased the requirement for platelet transfusions. In addition, the transfusion reactions ceased. Conclusion: In case of transfusion reactions against platelet products in major ABO-incompatible allo-HCT patients, isoagglutinin monitoring should be considered and a change in the platelet transfusion protocol may be beneficial in patients presenting high isotiters against recipient’s blood type.
Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular ...immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents ...(HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (
n
= 13) or decitabine (
n
= 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1–19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRD
neg
, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (
p
= 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (
n
= 24,
p
= n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (
p
= n.s.) and for patients with MR (not reached) compared to HR (3.4 months,
p
= 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
Multidrug-resistant bacterial pathogens (MRP) such as extended-spectrum beta-lactamase producing enterobacteriaceae (ESBL), vancomycin-resistant enterococci (VRE), methicillin-resistant ...Staphylococcus aureus (MRSA) and multi-resistant Pseudomonas aeruginosa (P. aeruginosa) are an emerging challenge in allogeneic hematopoietic cell transplantation (HCT). However, no comprehensive data are available on the prevalence of MRP, their impact on the outcome after HCT and on the probability to clear a MRP. It was the purpose of this study to systematically analyze the issue of MRP in HCT.
PATIENTS AND METHODS: From 07/2010 to 12/2015 a total number of 121 (43 F; 78 M) consecutive patients who received the first allogeneic HCT at our institution were analyzed retrospectively. As baseline investigation before conditioning all patients underwent a comprehensive screening for MRP. Swabs from nose, throat, axilla, urethra and anus as well as samples from stool and urine were collected. During the course of transplantation surveillance cultures were performed weekly. In addition, routine microbiological investigations were done from blood, urine, swabs, stool or central venous catheters whenever clinically needed. In MRP colonized patients surveillance stool specimen were taken until the MRP was repeatedly non-detectable. Multidrug-resistant gram neg. bacteria were categorized as 4MRGN (resistant to cephalosporins, piperacillin, fluorochinolones and carbapenems) or as 3MRGN (resistant to 3 of these 4 antimicrobial drug groups). The primary endpoint of this analysis was day 100 non relapse mortality (NRM). Secondary endpoints were NRM and overall survival (OS) after 2 years. A further endpoint in MRP+ patients was the time to non-detectability of the MRP.
RESULTS: The patient characteristics were as follows: Underlying diseases were AML (62), ALL (7), CML (8), MPN (5), lymphoma (9), MDS (25), and multiple myeloma (5). The conditioning regimen was myeloablative in 50, reduced intensity in 71 patients. Patients were transplanted with peripheral blood stem cells (105) or bone marrow (16) from matched siblings (28), matched unrelated (67), mismatched (15) or haploidentical donors (11). 33 patients (27%) were colonized by at least one MRP (MRP+ group) either at baseline (baseline MRP+ group, n=18, 15%) or at any other time point until day 100 post HCT. The 33 MRP+ group patients were colonized by 42 MRP (baseline MRP+ group: 19 MRP). Detected MRP were 3MRGN E. coli or Klebsiella pneumonia (17), 4MRGN (9) or 3MRGN (2) P. aeruginosa, multi-resistant Stenotrophomonas maltophilia (2), 3MRGN Citrobacter freundii (1), 3MRGN Acinetobacter baumanii (1), 4MRGN Enterobacter cloacae (2), VRE (7) and MRSA (1). Out of these 33 patients 12 (36%) developed an infection with an MRP after HCT: septicemia (n=9), pneumonia caused either by 3MRGN Klebsiella (n=1) or by 4MRGN P. aeruginosa (n=1) and urinary tract infection by 4MRGN Enterobacter cloacae (n=1). 5 patients died MRP related due to septicemia (4MRGN P. aeruginosa n=4, VRE n=1). However, day 100 and 2-year NRM of MRP colonized vs non-colonized patients were essentially the same: 15 and 21% vs 15 and 24%, respectively. Even for the baseline MRP+ group there was no significant difference of NRM: 17 and 29% vs 15 and 22%. Overall survival was also not impaired in the MRP+ group 2 years post HCT (median follow up 32.4 months, range 7.5 to 71.4 months): MRP colonized versus non-colonized patients: 60 vs 55% (baseline MRP+ group 54 vs 58%). Out of the 33 MRP+ group patients 21 patients were able to clear the MRP. On day 100 after HCT 36% of patients had been able to clear the MRP. Median time to non-detectability of the MRP was 6.3 months. In 12 patients the MRP did not disappear until the end of the observation period or death (median follow up 15 months). There was a highly significant (p<0.0001) survival difference between patients who cleared the MRP vs those with MRP persistence. Whereas 17 out of 21 (81%) patients who cleared the MRP survived, only 2 out of 12 patients with MRP persistence stayed alive (median survival 6.6 months). Day 100 NRM was 4 vs 42% (p=0.0023).
CONCLUSIONS: Since colonization by MRP had no neg. impact on the outcome in our cohort HCT of MRP colonized patients is feasible. However, the outcome of patients who do not clear their MRP is dismal. In order to increase the probability to clear the MRP we suggest to review the use of antibiotics in MRP colonized patients critically.
No relevant conflicts of interest to declare.
We report on patients who developed severe acyclovir-resistant (ACVr) herpes simplex virus 1 (HSV-1) stomatitis after allogeneic hematopoietic cell transplantation (HCT).
HCT patients suffering from ...HSV-1 stomatitis without response after 1 week of high-dose acyclovir (ACV) were tested for ACV resistance. Patients with proven ACV resistance were treated either topically with cidofovir solution and gel or with topical foscavir cream or with intravenous foscavir.
Among 214 consecutive HCT patients, 6 developed severe ACVr HSV-1 stomatitis (WHO grade III n = 1, WHO grade IV n = 5). All 6 patients suffered from relapse of acute myeloid leukemia (AML) after HCT. ACVr stomatitis was treated topically with first-line (n = 4) or second-line (n = 2) cidofovir. Topical foscavir cream was applied as first-line (n = 1) or second-line (n = 1) therapy. Intravenous foscavir was used in 3 patients (first-line therapy, n = 1; second-line therapy, n = 2). Complete remission was reached by topical cidofovir (n = 3), topical foscavir (n = 1), and intravenous foscavir (n = 1), respectively. Five of the 6 patients died due to progression of leukemia. Only 1 patient survived.
ACVr HSV-1 stomatitis is a severe complication in AML patients relapsing after HCT. It reflects the seriously impaired general condition of these patients. This analysis shows that topical treatment with cidofovir or foscavir might be a sufficient first-line therapy approach in ACVr HSV-1 stomatitis. It might serve as a less toxic alternative to intravenous foscavir.
▪
MRD in ALL is defined as the detection of leukemic cells in bone marrow below the microscopic threshold in complete remission (CR). Patients (pts) with molecular failure (MolFail) or molecular ...relapse (MolRel) after induction/consolidation therapy are at a high risk for hematologic relapse. Targeted therapies should prevent hematologic relapse, reduce MRD load and provide a bridging strategy to allogeneic stem cell transplantation (SCT) and thereby improve overall outcome of these pts. In pts without (wo) SCT option reduction of MRD load is an essential goal as well. Blinatumomab is an antibody construct that redirects CD3+ T cells to CD19+ target cells, resulting in a serial lysis of CD19+ B cells. In a study in pts with MRD ≥10-3, 78% achieved complete MRD response (Gökbuget N et al., Blood 2018). The MolAct1 trial was initiated by the GMALL study group to evaluate the efficacy and tolerability of Blinatumomab in MRD+ ALL including those with MRD below 10-3 and pts with MRD after SCT.
Adults (≥18 yrs) with CD19+, Ph-negative BCP ALL in CR after ≥ 3 chemotherapies with MRD ≥10-4 were eligible (NCT03109093). Recruitment of pts with MRD ≥10-3 was stopped after marketing authorization for this entity. After an amendment, which became effective after 44 recruited pts, pts with MRD below 10-4 or non-quantifiable (nq) MRD were eligible.
Blinatumomab 28 μg/day was given as 4-wk infusion, followed by a 2-wk break (1 cycle). Responders could receive up to 4 cycles or undergo HSCT after ≥ 1 cycle. MRD after 1 cycle was the primary endpoint. MRD was centrally assessed by allele-specific quantitative real-time PCR of clonal rearrangements of immunoglobulin or T-cell receptor genes. For definition of MRD at inclusion and at response assessment see table 1.
64 pts with a median age of 44 (18-83) yrs were included from 19 centers and 60 were evaluable. 63 pts were treated in first CR (5 after SCT). Overall, 67% achieved MolCR, 10% had MolFail, 23% MolNE. MolNE identifies an intermediate response with different options clarified table 1. 81% of the pts included with MRD ≥10-4 had a molecular response i.e. MolCR or MRD < 10-4. No significant differences in terms of MRD response were observed according to MRD level at inclusion or other patient characteristics (table 1).
60 pts have completed study treatment (40 HSCT, 8 relapses during treatment, 4 completed 4 cycles wo SCT, 2 stopped earlier due to toxicities - 1 with subsequent SCT, 1 due to GvHD, 1 due to physicians' decision and 4 pts returned to standard treatment after 2 cycles).
SCT pts had a median age of 42 (18-66) yrs and follow-up is available in 37 / 41 pts (29 CCR, 3 relapse, 5 death in CR).
16 relapses occurred: 8 during treatment (1 after MolCR, 5 MolNE1-3 and 2 with MolFail resp); after SCT in 3/41 pts; 5/11 with CR at end of treatment wo subsequent SCT.
The median observation time of surviving pts is 12 (1-38) mo and the median survival is not reached. At 2 yrs the survival probability (OS) was 64%. OS was 70%, 64% and 43% in pts with MRD between 10-4-10-3, 10-3-10-2 and >10-2 at inclusion, resp (p>.05; Fig.1). OS was 71% vs 54% in pts MolFail vs MolRel at inclusion (p>.05). OS was 72%, 40% and 56% in pts with MolCR, MolFail and MolNE after cycle 1 resp (P=0.02; Fig.2).
Overall, the results from previous trials were confirmed. In addition, it was demonstrated that pts with MRD between 10-4 and 10-3 had a similar response and a trend towards better outcome compared to pts with higher MRD levels >10-2. So far only 7 pts with MRD below 10-4 were included; more data are needed to evaluate the impact of Blinatumomab in this population; GMALL does currently not recommend SCT for these pts unless there is an indication due to other risk factors. Interestingly, a significant proportion of pts (23%) had an incomplete MRD response and the outcome results indicate that these pts together with those with MolFail may have an inferior survival compared to those with MolCR. The results underline that the clear definition of MRD categories and consideration of level and sensitivity is essential for interpretation, which is possible due to well defined standards for the PCR method used here. 68% of the pts received SCT in CR after Blinatumomab with a so far limited mortality (13%). Further follow-up is certainly required. The GMALL will continue to recruit patients with MRD levels below 10-3 in order to improve their chances for long-term survival
This study was supported by Amgen Inc.
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Goekbuget:Servier: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Erytech: Consultancy; Kite: Consultancy; Gilead: Consultancy. Schwartz:Pfizer: Other: personal fees; AMGEN: Other: personal fees and non-financial support; BTG Intl Inc: Other: personal fees; Gilead Sciences: Other: personal fees and non-financial support; MSD Sharp & Dohme: Other: personal fees; Basilea: Other: non-financial suppor; Novartis: Other: personal fees and non-financial support; Jazz Pharmaceuticals: Other: personal fees and non-financial support. Hüttmann:Lead Discovery Center GmbH: Consultancy; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria. Viardot:Roche: Honoraria, Other: advisory board; Kite/Gilead: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Amgen: Honoraria, Other: advisory board. Fiedler:Daiichi Sankyo: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Jazz Pharmaceuticals: Honoraria, Other: support for meeting attendance; Abbvie: Membership on an entity’s Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; ARIAD/Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: support for meeting attendance, Patents & Royalties, Research Funding. Alakel:Pfizer: Consultancy. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Subklewe:Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Morphosys: Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy; Roche AG: Consultancy, Research Funding. Wäsch:Pfizer: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Vucinic:Celgene: Honoraria. Fransecky:Amgen: Consultancy. Bargou:Amgen: Consultancy, Honoraria, Patents & Royalties; Gemoab: Consultancy, Honoraria; Cellex: Consultancy, Honoraria; Catalym: Consultancy, Honoraria. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Brüggemann:Regeneron: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Incyte: Consultancy; Roche: Consultancy; Affimed: Research Funding; Janssen: Consultancy, Honoraria.
Blinatumomab in MRD positive disease below 10-3
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