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Multiple myeloma (MM) is characterized by recurrent relapses. Consequently, patients receive multiple therapy lines, including alkylating agents and immune modulators, which have been associated with secondary malignancies such as myelodysplastic syndrome (MDS). Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy is efficacious in patients with relapsed/refractory (R/R) MM. However, the long-term complications, particularly MDS, are not well understood. Whether CART therapy causes or promotes MDS has not been thoroughly investigated. In this study, we explored the causal relationship between MDS and CART therapy. We retrospectively examined the prevalence of MDS-related morphological and mutational changes before and after administration of CART therapy in five patients. Among them, four developed MDS after CART therapy, while one had pre-existing MDS prior to CART. None of the four patients who developed post-CART MDS showed morphological MDS changes prior to CART therapy. However, all four patients exhibited molecular alterations associated with MDS in their pre-CART as well as post-CART therapy bone marrow. No new mutations were observed. Our findings provide initial evidence suggesting that anti-BCMA CART therapy in MM may promote expansion of pre-existing MDS clones rather than causing development of new clones.

Purpose:AL amyloidosis (AL) treatments are generally based on those employed for multiple myeloma. Anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T (CART)-cell therapy, already approved for multiple myeloma, might be too toxic for patients with AL.Experimental Design:Here we describe the ex vivo applicability of a novel in-house, academic anti-BCMA CAR construct on AL primary cells, as well as the safety and efficacy in 4 patients with relapsed/refractory (RR) primary AL, treated in a phase I clinical trial (NCT04720313).Results:Three had MAYO stage IIIa cardiac involvement at enrollment. The treatment proved relatively safe, with a short and manageable grade 3 cytokine release syndrome evident in 2 patients and no neurotoxicity in any. Cardiac decompensations, observed in 2 patients, were also short and manageable. The overall hematologic response and complete response rates were observed in all patients with an organ response evident in all four. Within a median follow-up period of 5.2 (2.5–9.5) months, all 4 patients maintained their responses.Conclusions:BCMA-CART cells provide a first proof-of-concept that this therapy is safe enough and highly efficacious for the treatment of patients with advanced, RR AL.

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The optimal high-dose methotrexate (HDMTX)-based combination therapy for primary central nervous system lymphoma is unknown. We report our experience with rituximab, HDMTX, procarbazine and lomustine (R-MPL) given as first-line treatment in our center. Fifty-two patients between 2006 and 2019 were included. Eighteen patients proceeded to autologous transplant or two cycles of intermediate-dose cytarabine. The median age was 62 y (range 28-94) and the Eastern Cooperative Oncology Group performance status (ECOG-PS) was ≥2 in 62% (32/52). The overall/complete response rates were 79% (41/52) and 52% (27/52), respectively. The median progression-free/overall survival was 19 m/84m, respectively. Grade 3-4 adverse events included infections (17%) and kidney injury (13%). Ten patients (19%) discontinued therapy for toxicity. There were no treatment-related deaths. In summary, in a cohort enriched in frail patients, R-MPL achieved good responses and OS and was safe for all ages. The PFS was sub-optimal, possibly explained by a low proportion of consolidation. This regimen should be evaluated prospectively.

We present a patient with amyotrophic lateral sclerosis (ALS), dependent on noninvasive ventilation, whose advance directives precluded life-prolonging measures. The patient was found in cardiac arrest and in accordance with the directives of her surrogate decision maker, underwent intubation and mechanical ventilation. Later, an additional surrogate decision maker disapproved of ventilation and when the ventilator was disconnected for bronchial suctioning, she asked the nurse not to reconnect the patient to the ventilator. We discuss the legal, psychological and ethical aspects of implementation of Israeli law in this complex patient.

ObjectiveInterprofessional care is integral to end-of-life (EOL) and palliative care (PC) and may be suited for EOL and PC education.We evaluate the impact of an interprofessional EOL care curriculum on participants, during the course, on completion and 4 years laterusing quantitative (questionnaires) and qualitative (open-ended questions and interviews) methods.The course included 14 fifth and sixth-year medical students, 9 social work students and 7 nursing students enrolled in master’s degree programmes. Seventeen participants completed questionnaires 4 years later and eight participated in interviews.On postcourse questionnaires, participants attributed high value to interprofessional education (IPE) (4.77/5±0.50 on a Likert scale). Four years later, participants reported that IPE impacted their professional (3.65/5±1.11) and personal lives (3.94/5±1.09) and found PC IPE important (4.88/5±0.33).Conventional content analysis showed that the course enabled discussion of death and dying and provided an opportunity for a personal-emotional journey. It offered an approach to EOL care and an opportunity to experience interprofessional teamwork at the EOL resulting in behavioural change.Interprofessional EOL education resulted in meaningful and lasting self-reported personal and professional behavioural outcomes.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti-BCMA CART cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1, 150x10^6 CART cells, N=6; cohort 2; 450x10^6 CART cells, N=7 and cohort 3, 800x10^6 CART cells, N=7) (NCT04720313) in 20 heavily pretreated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS, nor neurotoxicity of any grade were observed. No dose-limiting toxicities (DLTs) were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR) and very good partial response (VGPR) rates were 75%, 50% and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR and 57% minimal residual disease (MRD) negativity in the high-dose cohort 3. For the entire cohort, the median overall survival (OS) was 308 days (range, 25-466+), with an estimated OS of 55% as of data cutoff June 27th. The median progression-free survival (PFS) was 160 days, with 6 subjects remaining progression free at the time of data cutoff. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These favorable data are encouraging and support decentralization of CART production at an academic setting, ensuring a sufficient CART supply in the light of the increasing local demand.

Remission assessment in acute myeloid leukemia has evolved over the recent years with the advent of molecular and flow-based minimal residual disease determination. Nonetheless, early time point such as day 5 and day 14 (D14), still have prognostic and therapeutic implications. D14 refractory disease is regarded as a poor prognostic factor, however the therapeutic intervention is still under debate, with evidence suggesting a successful re-induction might offer similar long-term outcome as D14 aplasia. Others advocate the use of more intensive salvage protocols as a mean to overcome the negative prognostic effect. In the current study, we compare outcome of D14 refractory AML patients treated with either re-induction or salvage protocol. More importantly, we identify response characteristics that might suggest which patients will benefit from re-induction approach. Accurate identification of chemotherapy refractory patients might allow the early incorporation of non-chemotherapy based protocols in the future.

Early palliative care (EPC) significantly improves quality of life, symptoms, and satisfaction with care for patients with advanced cancer. International organizations have recognized and promoted the role of palliative care as a distinct specialty, advocating its involvement throughout the cancer trajectory. Although patients with haematologic malignancies (HMs) have a comparable symptom burden to patients with solid tumours, they face multiple barriers to EPC integration. In this review, we discuss these barriers, present updated evidence from clinical trials of EPC in HMs and propose models to support EPC integration into care for patients with HMs.

Background: End-of-life (EoL) Care is challenging for terminally-ill patients and their caregivers. This research is aimed to examine the relational agencies of the patients, the caregivers, and the medical teams in the context of EoL care, with a particular emphasis on the caregivers. Methods: This study is based on the qualitative analysis of interviews with 12 individuals who were closely supported a loved one to their death from a terminal illness. Results: Information collected revealed several agency-related themes. Family caregivers are significant entities in managing the ‘case’ of a seriously ill individual. At the final or more advanced stages of the EoL process, caregivers gradually shift from a supportive role to being active agents, but not always backed by the necessary experience, knowledge, or the requisite emotional resilience. Conclusions: Based on recognizing their agentic proactivity, a clear and elaborate articulation of the family caregivers' roles is needed.

Purpose: AL amyloidosis (AL) treatments are generally based on those employed for multiple myeloma. Anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T (CART)-cell therapy, already approved for multiple myeloma, might be too toxic for patients with AL. Experimental Design: Here we describe the ex vivo applicability of a novel in-house, academic anti-BCMA CAR construct on AL primary cells, as well as the safety and efficacy in 4 patients with relapsed/refractory (RR) primary AL, treated in a phase I clinical trial (NCT04720313). Results: Three had MAYO stage IIIa cardiac involvement at enrollment. The treatment proved relatively safe, with a short and manageable grade 3 cytokine release syndrome evident in 2 patients and no neurotoxicity in any. Cardiac decompensations, observed in 2 patients, were also short and manageable. The overall hematologic response and complete response rates were observed in all patients with an organ response evident in all four. Within a median follow-up period of 5.2 (2.5–9.5) months, all 4 patients maintained their responses. Conclusions: BCMA-CART cells provide a first proof-of-concept that this therapy is safe enough and highly efficacious for the treatment of patients with advanced, RR AL.

Signal transducer and activator of transcription (STAT)1 heterozygous gain-of-function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In-depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non-consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58–24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole-exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in four of the five patients. Immunophenotyping demonstrated increased phosphorylated signal transducer and activator of transcription in response to interferon-α stimuli in all patients. The patients also exhibited decreased T cell proliferation capacity and low counts of interleukin-17-producing T cells, as well as low forkhead box protein 3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, the management of patients with chronic demodicosis should include an immunogenetic evaluation.

Background Major advances in the treatment of patients with hairy cell leukemia (HCL) have been made following the introduction of purine analogues. The major significant short-term toxicity of cladribine therapy are neutropenia and neutropenic fever (NF) which may be life-threatening. Aim In this retrospective study, we compared the incidence and duration of neutropenia and hospitalization in patients with HCL treated with cladribine followed by peg-filgrastim as primary prophylaxis versus daily filgrastim given “on demand” according to absolute neutrophil count (ANC). Methods Medical records of patients with HCL diagnosed and followed in 12 medical centers in Israel during 1985–2015 were examined for details of disease at diagnosis. The efficacy of peg-filgrastim and filgrastim was assessed by evaluating the incidence of neutropenia (ANC 9 ]/L), number and length of hospitalizations, and number of days from the last day of therapy to recovery of ANC to >1.0 × 10 [ 9 ]/L. Results The study population included 202 patients with HCL, 159 of whom (80.7%) were treated with cladribine; 78 patients (49%) required hospitalization for the administration of broad-spectrum antibiotics due to NF. Twenty-eight (19%) patients were treated with peg-filgrastim as primary prophylaxis, while 74 (64%) received filgrastim “on demand” due to neutropenia. Median length of hospitalization, and nadir duration were 8 and 18 days respectively (p = 0.71, p = 0.44). Conclusions Infectious complications post-cladribine treatment remain high. No difference was found in terms of incidence of NF, number of febrile days, and nadir duration in patients receiving primary peg-filgrastim prophylaxis compared to filgrastim given on demand. Both approaches are justifiable, and the choice remains at the physician’s discretion.

Combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is regarded as standard care for diffuse large B-cell lymphoma (DLBCL) and upfront intensification of therapy is still controversial. The current study aimed to dertermine whether the addition of high-dose methotrexate (HDMTX) affects long-term outcomes and could also prevent central nervous system (CNS) relapse. Medical records of 480 patients with DLBCL treated between 1994 and 2013 at Rambam and Hadassah medical centers in Israel were reviewed; 130 (27%) had received HDMTX. Patients receiving HDMTX generally had higher International Prognostic Index (IPI) and CNS-IPI scores. HDMTX addition significantly improved progression free and overall survival (

Background: One of the main obstacles of providing home-based palliative care to transfusion-dependent hematology patients is the lack of home transfusions services. While healthcare professionals are concerned with safety and cost of home transfusions, the attitude of the patients toward home transfusions are mostly unknown. Aim: To obtain quantitative data regarding the willingness and concerns of transfusion-dependent patients with hematological diseases toward the option of home transfusions. Design: A cross sectional survey including a self-administered questionnaire in one of the three main spoken languages in Israel was administered to patients in 17 hospital hematology outpatient clinics between May 2019 and March 2020. Results: About 52% of 385 patients that participated in the survey preferred home transfusions to hospital transfusions. Gender, age, education, or type of disease were not associated with preference for home transfusions, nor were hospital location or its size. The likelihood to prefer home transfusions was significantly higher among the Hebrew-speakers and those who had not experienced adverse effects previously. The most significant factor associated with preference of home transfusions was a perceived negative effect of hospital-based transfusion on quality of life. The main reason to reject home transfusions was fear of possible adverse effects and concerns over losing contact with the medical staff at the treating hospital. Conclusion: These data suggest that a significant portion of transfusion-dependent patients in Israel view home transfusions as a preferred treatment option and that its successful implementation requires maintaining ongoing contact with the treating hospital.

ObjectiveHemato-oncologists are highly exposed to patients’ death and suffering during their daily work. The current exploratory and cross-sectional study examined death acceptance attitudes, in order to explore whether death acceptance attitudes are associated with fear of death.MethodA convenience sample of 50 Israeli hemato-oncologists currently working in a clinical setting participated in the study. They completed the Death Attitudes Profile revised questionnaire (DAP-R), which examines levels of fear of death, death avoidance, approach acceptance, neutral acceptance, and escape acceptance. In addition, the hemato-oncologists reported on levels of exposure to patients’ death and suffering.ResultsA repeated measures MANOVA revealed significantly lower levels of neutral acceptance, compared with approach and escape acceptance. Path analysis for predicting fear of death by the other study variables revealed that death avoidance fully mediated the relationship between approach acceptance and fear of death as well as revealing a negative correlation between neutral acceptance and fear of death (higher neutral acceptance was related to lower fear of death). No associations were found between exposure to death and suffering and attitudes toward death.Significance of resultsIn contrast to previous conceptualizations, the ability to adaptively cope with fear of death differed in accordance with death acceptance attitudes. Whereas neutral acceptance adaptively defended from fear of death, approach acceptance was associated with increased fear of death through death avoidance. As hemato-oncologists are highly exposed to patients’ death and suffering, and are required to make critical medical decisions on daily basis, these findings may have substantial implications for end-of-life care and the process of medical decision-making regarding the choice of treatment goals: cure, quality of life, and life prolongment. Further research is needed to investigate the role of death acceptance attitudes among hemato-oncologists.

Background Most cancer patients prefer to die at home; however, many die in hospital. The aim of the current study is to elucidate the association between dying at home and various personal factors in the Israeli population of cancer patients. Methods Data on cancer incidence (2008–2015) and death (2008–2017) was provided by the Israeli Central Bureau of Statistics and the Israel National Cancer Registry. Binary logistic regression analyses were performed to assess odds ratios for death at home following cancer diagnosis while controlling for age, sex, ethnicity, years of education, residential socioeconomic score, and time from diagnosis. We also assessed the relation between place of death and specific cancer sites, as well as the time trend from 2008 to 2017. Results About one quarter (26.7%) of the study population died at home. Death at home was most frequent among patients diagnosed with brain tumors (37.0%), while it was the lowest among patients with hematologic malignancies (lymphoma and leukemia, 20.3 and 20.0%, respectively). Rates of dying at home among patients with residential socioeconomic scores of 1, 2–9, and 10 were about 15, 30, and 42.9%, respectively. In patients from the 4th to the 7th decades of life, rates of death at home increased at a linear rate that increased exponentially from the 8th decade onwards. After controlling for potential confounders, predictive variables for death at home included age (OR = 1.020 per year, 95% CI 1.017–1.024), male sex (OR = 1.18, 95% CI 1.077–1.294), years of education (OR = 1.029 per year, 95% CI 1.018–1.040), and time from diagnosis (OR = 1.003 per month, 95% CI 1.001–1.005 all p Conclusions These results indicate wide variability in death at home exists among patients of different ages, sex, education, socioeconomic status and time from diagnosis. These findings stress the importance of delivering quality palliative care at home, mainly for patients with hematologic malignancies, younger patients, and patients of very low socioeconomic status. Understanding the complex mechanisms whereby patient preferences and the above variables may determine the preferred place of death remains an important research priority.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Palliative care is an approach meant to improve the quality of life of patients facing life-threatening illness and to support their families. An international workshop on palliative care took place in Caesarea, Israel under the auspices of the National Institute for Health Policy Research on July 4-5th, 2018, with the goal of discussing challenges to the development and integration of palliative care services in Israel. At the workshop, both national and international figures in the field of palliative care and health policy addressed several issues, including truth telling, religious approaches to end of life care, palliative care in the community, pediatric palliative care, Israel’s Dying Patient Act, the Ministry of Health’s National Plan for palliative care, and challenges in using advance directives. We summarize the topics addressed, challenges highlighted, and directions for further advancement of palliative care in the future, emphasizing the critical role of the Ministry of Health in providing a framework for development of palliative care.

The treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) presents a true clinical challenge. In 2012, a protocol combining bortezomib, dexamethasone, asparaginase, doxorubicin, and vincristine administered to children with RR-ALL was published with encouraging results. Over the past 5 years, we have implemented this protocol in the adult RR-ALL population (> 18 years) and addressed its feasibility in terms of remission rate and toxicity. Here, we present the results of our experience in 9 patients, all of whom received multiple previous chemotherapy protocols, two of them relapsing after an allogeneic bone marrow transplantation. All of the five B-ALL patients, and two of the four T-ALL achieved complete remission. Of the seven patients achieving complete remission, two patients were referred for allogeneic bone marrow transplantation, two patients were subsequently given blinatumomab, and one patient subsequently received donor lymphocyte infusion followed by blinatumomab. Thus, five out of nine patients treated (55%) were able to proceed to best available therapy in a complete remission. We observed minimal adverse effects, mainly hematological toxicity. We conclude that the bortezomib-based protocol should be evaluated as an effective and well-tolerated treatment option for adult patients either unfit for or failing standard salvage chemotherapy, as a bridge to immunotherapy or allogeneic bone marrow transplantation.

Previous studies and meta-analyses addressing COVID-19 in patients with hematological malignancies (HM) have reported dramatically high mortality rates of up to 34% [Vigenthira 2020, Garcia-Suarez 2020, Sharafeldin 2021]. These studies, however, were strongly biased towards hospitalized patients, and poorly represented patients who experienced a milder course of COVID-19, not requiring hospitalization. Jerusalem and its metropolitan area, comprising of over 1.3 million inhabitants, was the epicenter of Israel's COVID-19 crisis, with over 200,000 cases. Hadassah Medical Center, one of only two tertiary centers serving this multi-ethnic population, houses a Hematology Department that includes inpatient services, a hematopoietic stem cell transplant (HSCT) center, day care services and in-campus outpatient clinics. From February 20 th, 2020, we tracked patients with confirmed COVID-19 reporting to their treating hematologists while being hospitalized due to COVID-19, at routine visits to the hematology services, or remotely via phone or email communication. This assured the representation of COVID-19 cases of various clinical severities. Data were collected retrospectively and included demographics, comorbidities, hematological diagnoses and treatments, course of COVID-19 and, importantly, source of infection. Univariate and multivariate analyses were used to assess association between prognostic factors and outcomes including hospitalization, severe COVID-19 (per updated WHO criteria) and critical COVID-19, defined as a composite of ICU admission and mortality. Almost all the patients in this series were diagnosed prior to their vaccination. To the best of our knowledge, this is the largest single center series of HM patients with COVID-19 reported to date. Our series included 183 patients. Median age was 62.5 years, 57% were men, and 72% had at least one comorbidity. The most frequent hematological diagnoses were indolent lymphoma and CLL (40%), aggressive lymphoma (20%) and multiple myeloma (19%). At the time of COVID-19 diagnosis, 41% of the patients were receiving systemic anti-neoplastic treatment (excluding TKIs for CML and hydroxyurea for MPN), and 16% had undergone a previous allogeneic or autologous HSCT. Overall mortality, severe COVID-19, and hospitalization rates in the entire group were 9.8%, 14.2% and 32%, respectively, remarkably lower than in previous reports. Of the patients not receiving anti-neoplastic treatment, mortality and severe COVID-19 rates were comparable to those of the age-matched general population according to the Israeli Ministry of Health database [Table 1]. Consistent with previous studies, ischemic heart disease (IHD), dyslipidemia, chronic kidney disease, smoking and hypertension, as well as age and active anti-neoplastic treatment, each emerged as a risk factor significantly associated with hospitalization due to COVID-19 [Fig. 1, Table 2]. IHD, smoking, age and active treatment remained significant in multivariate analysis. Age and active treatment as well as ≥4 comorbidities were significantly associated with critical COVID-19. Interestingly, we observed a strong association between the number of prior anti-neoplastic treatment lines and critical COVID-19. Neither history of HSCT nor treatment with monoclonal antibodies were associated with COVID-19 outcomes. Notably, we did not detect any patient that contracted COVID-19 within the Hematology Department services, both inpatient and outpatient. Taken together, we present a different COVID-19 severity landscape in patients with HM as compared to previous observations. While active treatment was significantly associated with COVID-19 hospitalization and mortality, these rates were remarkably lower than previously reported. Despite harboring various degrees of immune suppression, patients with stable or indolent diseases not receiving active treatment appeared to be at a risk comparable to that of the age-matched general population, which depended largely on age and comorbidities. Routine preventive measures including symptom questioning, masks, and social distancing in both our inpatient and outpatient services provided a COVID-19-safe environment, obviating the need for changes in treatment schedules or assignment. These findings may have important consequences for future management of patients with HM in COVID-19 affected regions. Figure 1 Figure 1. Disclosures Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures; Takeda: Consultancy. Goldschmidt: AbbVie: Consultancy, Research Funding.

Gastrointestinal (GI) perforation is remarkably rare in patients with light chain (AL) amyloidosis and has not yet been reported in patients with AL amyloidosis treated with novel agents. Only 24 cases of GI perforation have previously been reported in the setting of AL amyloidosis of which 15 had available information in English. All 15 did not receive novel agent therapy and six died early after experiencing GI perforation. This study reports the characteristics and outcome of AL patients that developed GI perforation in the era of novel agent treatment. Seven patients were reviewed. In two patients, GI perforation was the presenting symptom of AL amyloidosis, whereas five patients developed GI perforations following initiation of an anti-AL therapy (three after bortezomib-based, 1 after lenalidomide-based and 1 after thalidomide-based therapy). All patients underwent surgery and survived the perforation. Treatment was renewed following surgery in six of seven patients, with no further GI complications. In conclusion, GI perforation in AL amyloidosis is rare and mostly reported after treatment initiation. Urgent surgery appears to be lifesaving and renewal of the anti-AL novel therapy appears to be safe, with no significant risk for re-perforation or GI toxicity. Prognosis in these patients is related to severity of the disease and response to therapy rather than the development of GI perforation.

Introduction: Primary central nervous lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma that may involve the brain, spinal cord, leptomeninges and vitreous. The median age at diagnosis is in the fifth decade and most patients (pts) present with significant neurologic deficit and a low performance status. The optimal treatment of PCNSL is controversial. High dose methotrexate (HDMTX) is a standard treatment of PCNSL and is more effective when given in combination with other CNS-penetrating medications, which, however, add to the toxicity of the treatment. We aimed to evaluate the effectiveness and the safety of the combination of rituximab, HDMTX, procarbazine and lomustine (R-MPL) in pts with PCNSL. Patients and methods: We retrospectively reviewed the files of PCNSL pts treated in Hadassah Medical Center, Jerusalem, Israel, between the years 2006-2019. The medical records were reviewed for demographic details and initial disease characteristics (age, sex, performance status, laboratory results, cerebrospinal fluid (CSF) content and tumor location), and for therapeutic details including chemotherapy protocol, toxicity, response to treatment and survival. We excluded pts who could not receive HDMTX. The R-MPL is a 42-day cycle protocol, consisting IV Rituximab 375 mg/m2 on days 1, 15 and 28, IV HDMTX 5 g/m2 (3.5 g/m2 for pts > 60 Years (y)) on days 2, 15 and 29, PO procarbazine 100 mg/m2 (60 mg/m2 for pts > 60 y) on days 3-9, PO lomustine 60 mg/m2 (40 mg/m2 for pts > 60 y) on day 2. Six to nine intrathecal (IT) injections of MTX / cytarabine were included for pts with positive CSF cytology, tumor adjacent to ventricles, or per physician's decision. Rituximab was given for no more than 8 doses in total. A total of 3-4 courses of R-MPL were given. Responsive pts could proceed to autologous stem cell transplant (ASCT) with TECAM conditioning or 2 cycles of intermediate dose cytarabine (IDAC, 1.5 g/m2), 2 doses in each cycle. Those who achieved less than CR or had significant toxicity to R-MPL received additional ifosfamide/etoposide or high dose cytarabine or temazolamide or topotecan. Radiation was given only for salvage. Results: Fifty-two pts were included in the study. Median age was 62 years (range 28-94). Three (6%) had leptomeningeal involvement, thirteen (25%) had vitreoretinal involvement, 30 (58%) had involvement of the deep brain. Mean ECOG, IELSG and MSKCC scores were 1.98, 2.53 and 1.94 respectively. The median number of HDMTX doses was 8 (range 3-16). Forty-five (87%) pts completed at least one 42-day cycle of R-MPL. Among this group, 29 (64%) pts received at least 3 IT injections, 12 (27%) underwent ASCT, 10 (22%) received IDAC, and 7 (16%) received other chemotherapies. The median follow-up was 27 months (m) (range 0.4-140m). The overall response rate (ORR) was 79% (41/52), and the complete response (CR) rate was 52% (27/52). The median progression free survival (PFS) was 15.5m and the median overall survival (OS) was 27m. Among the 45 pts who received at least one R-MPL cycle, the ORR was 87% (39/45), the CR rate was 60% (27/45), the median PFS was 84m and the median OS was not reached (figure 1). Known prognostic factors correlated with OS: age (p ASCT/IDAC did not improve PFS/OS, however numbers were small. Achieving CR at the end of treatment strongly correlated with PFS/OS, but timing of best response (after one 42-day cycle Vs later) did not. Grade 3-4 adverse events included infections (21%) and kidney injury (13%). Two pts died during therapy, both in the 1st cycle due to disease progression. Ten pts (19%) discontinued therapy due to toxicity. No treatment related mortality (TRM) was documented. Conclusions: The R-MPL protocol achieved a favorable ORR/PFS/OS as described, with reasonable grade 3-4 toxicity and no TRM. The advantage of ASCT/IDAC could not be assessed due to small number of pts. IT injections (at least 3) and achievement of CR at the end of treatment correlated with survival. The R-MPL protocol was reported in previous trials only among the elderly, and should further be evaluated in all age groups. Disclosures Goldschmidt: Abbvie Inc: Consultancy, Research Funding.

Multiple myeloma (MM) and primary systemic light chain amyloidosis (AL) are both chronic plasma cell dyscrasias with different clinical expression but limited treatment options for relapsed refractory disease. We report the effect of the addition of clarithromycin on 31 MM and 17 AL with relapsed or refractory disease who had an insufficient response or disease progression while on an IMiD based therapy. In this high risk population, hematological response was reported in 48% of MM patients and 94% of AL patients. Responses were reported early in both groups (median 35 days) and were more sustained in AL patients. Adverse events were common and included mostly grade 1-2 fatigue, infections and abdominal discomfort. Cytopenias were common and cardiac complications were rare in both MM and AL patients. Clarithromycin-IMiD combination therapy appears to be both effective and safe in progressive MM and primarily in AL patients, although a prospective clinical trial is warranted to validate these results. Am. J. Hematol. 92:131-135, 2017. © 2016 Wiley Periodicals, Inc.

Ixazomib, the first oral proteasome inhibitor (PI), has been approved for the treatment of relapsed refractory multiple myeloma (RRMM) in combination with lenalidomide and dexamethasone, based on the TOURMALINE-MM1 phase 3 trial, which demonstrated the efficacy and safety of this all-oral triplet, compared with lenalidomide-dexamethasone. However, clinical trial outcomes do not always translate into real-world outcomes. The aim of this study was to assess the outcomes of ixazomib-based combination for treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least one cycle of ixazomib-based treatment combination between June 2013 and June 2018 were identified. Data was extracted from medical charts focusing on demographics, disease characteristics, prior treatment, and responses. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), safety, and tolerability. A total of 78 patients across 7 sites were retrospectively included. Median follow-up was 22 months. Median age was 68 (range 38–90). Sixty-four percent received ixazomib in 2nd line, 19% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 87%) prior to IRd, 41% to IMiDs. Twenty-nine (48%, of 60 available) had high (t(4:14), t(14:16), del17p) or intermediate (+1q21) risk aberrations. Most patients (82%) received ixazomib in combination with lenalidomide and dexamethasone. An exploratory assessment for disease aggressiveness at diagnosis was classified by a treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 37%, respectively. Treatment was well tolerated, with a low discontinuation rate (11%). Median PFS on ixazomib therapy was 24 months (95% CI 17–30). PFS was 77% and 47% at 12 and 24 months, respectively. Median OS was not reached; OS was 91% and 80% at 12 and 24 months, respectively. Higher LDH, older age, and worse clinical aggressiveness were associated with worse PFS, whereas a deeper response to ixazomib (≥ VGPR) and a longer response to first-line bortezomib (≥ 24 m) were associated with an improved PFS on ixazomib. No effect on PFS was found for cytogenetic risk by FISH, ISS/rISS, and prior anti-myeloma treatment. Ixazomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting, regardless to cytogenetic risk, with a PFS of 24 months comparable with clinical trial data. This regimen had most favorable outcomes among patients who remained progression-free more than 24 months after a bortezomib induction and for those who have a more indolent disease phenotype.

Purpose Mucormycosis is a rare opportunistic and aggressive deep fungal infection that predominantly affects immunocompromised patients, and its mortality rate has been reported as up to 80%. Typing of the infection is based mainly on clinical and anatomic presentations, with the most common being the rhinocerebral type. Materials and Methods This report presents 3 patients with cancer who had successful treatment of mandibular mucormycosis. Chemotherapy was administered 13 to 30 days before diagnosis of the infection, resulting in neutropenia in all patients. Each case is thoroughly presented from initial admission through its diagnosis and treatment sequence. Results Early surgical ablative treatment and antifungal treatment resulted in the resolution of infection in all patients. Absolute neutrophil count increased 7 to 8 days after surgical debridement. Conclusions Bringing patients to the post-neutropenic state tremendously increases their odds for survival.

Background: The treatment of relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) is limited to a few agents. Romidepsin, a histone deacetylase inhibitor, was approved for PTCL treatment as a single agent in the R/R setting, yet with partial efficacy. Several attempts to combine romidepsin with other chemotherapy regimens have been reported, however, with significant toxicity. Objectives: To study the romidepsin-bendamustine combination in PTCL in an attempt to maximize efficacy while minimizing toxicity. Methods: We report on a series of 7 heavily pretreated PTCL patients (2–5 previous lines of therapy) treated with a romidepsin-bendamustine combination. Results: Four patients were not previously exposed to either drug. Of these, 2 achieved complete remission. Interestingly, 1 patient continued treatment with a prolonged progression-free survival of more than 4 years. Toxicity was minimal and no treatment-related deaths or discontinuation were noted. Significant nausea and vomiting were reported in over 50% of patients. Hematological toxicity was mild and lower than that reported for other romidepsin-chemotherapy combinations and was correlated with bone marrow involvement by lymphoma. Conclusions: Although reporting a small number of patients, our data suggest that the combination of romidepsin and bendamustine may be a feasible therapeutic option in R/R PTCL patients and merits further study.

A 38 years old male patient of Arab origin was transferred to our hospital in 2016 suffering from a relapse of Hodgkin's lymphoma (HL), which was confirmed by a cervical lymph node biopsy. The pati...

Multiple myeloma (MM) patients presenting with anaemia as their sole clinical manifestation are rare and not fully defined.Retrospective multi-site study comparing the characteristics and outcome of MM patients with anaemia only with matched patients, presenting with multi-organ disease.Anaemia-only patients had a higher percentage of bone marrow monoclonal plasma cells group (median 60% [IQR 42-80%] vs. 37% [IQR 17-65%], respectively; p0.001), and a lower responsiveness to treatment (≥VGPR rates were 54% vs 74%, p = 0.049). Median survival in anaemia only patients was 65.9 ± 6.9 vs 83.4 ± 8.8 months in matched control patients (P = n.s).MM patients presenting with anaemia only represents a unique, potentially less favorable population.

Objectives To evaluate the quality of end-of-life (EOL) care in nursing homes. Design Survey and semistructured interviews. Setting Jerusalem district nursing homes. Participants Staff members of 28 long-term care and skilled nursing facilities in the Jerusalem area in Israel of various ethnic, religious, and administrative affiliations (N = 207). Measurements Qualitative analysis of semistructured interviews and statistical analysis of questionnaires. Results Most staff members reported that EOL preferences were unknown for more than 90% of residents and that fewer than 10% had a healthcare proxy. Most staff members recalled conducting fewer than five EOL conversations over the past year with residents or family members and could recall fewer than five cases in which a resident was allowed to die in the nursing home. According to staff opinions the prevalence of tube feeding was estimated at greater than 10%, initiated because of aspiration, malnutrition, and understaffing, often against family's preferences. More than 25% of staff members believed that pain management was inadequate. Knowledge about management of chronic pain was poor in half of nurses and nearly one-third of physicians. Most staff would rather not receive the treatments they administered to residents. Conclusion Nursing homes in Jerusalem lack competency for quality EOL care, and there are multiple psychological, training, and policy challenges to improvement.