Refractory Thrombotic Thrombocytopenic Purpura Research Articles

PB0337 Occult Cervical Cancer-Induced Refractory Thrombotic Thrombocytopenic Purpura in a Renal Transplant Patient with Low- level Cytomegalovirus Viremia: A Case Report

PB0337 Occult Cervical Cancer-Induced Refractory Thrombotic Thrombocytopenic Purpura in a Renal Transplant Patient with Low- level Cytomegalovirus Viremia: A Case Report

PB0336 Refractory Thrombotic Thrombocytopenic Purpura Treated by Discontinuation of Therapeutic Plasma Exchange

PB0336 Refractory Thrombotic Thrombocytopenic Purpura Treated by Discontinuation of Therapeutic Plasma Exchange

N-Acetylcistein for thrombotic thrombocytopenic purpura: an observational case series study.

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. N-Acetylcysteine (NAC) rapidly degrades ultra-large von Willebrand factor multimers by disrupting the disulfide bonds. We report a series of twelve consecutive patients diagnosed with acquired TTP successfully treated with high-dose NAC (150 mg/kg/day) in combination with plasma exchange and steroids. Eight patients also received rituximab. Two patients presented refractory TTP. All patients achieved a quick clinical response in a median time of 5.5 days after starting NAC and are alive after a median follow-up of 29 months. The treatment was feasible and well tolerated. These data provide further evidence of the potential benefit and safety of adding NAC to the standard of care.

Use of n-acetylcysteine therapy in patients with relapsed refractory thrombotic thrombocytopenic purpura

There is limited data on the use of NAC in the literature. We would like to present the satisfactory results we obtained in our resistant and relapsed patients as a case series.Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by ADAMTS13 (a disintegrin with thrombospondin type 1 motif and metalloprotease activity, member13) deficiency. Von Willebrand factor (vWF) initiates platelet aggregation and thus thrombus formation. The multimers of vWF are cleaved by ADAMTS13. Because of the decreased activity of ADAMTS13, ultra-large multimers accumulate and end-organ damage occurs. TTP is characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and organ ischemia resulting from vascular occlusion caused by thrombi. Plasma exchange therapy (PEX) remains the mainstay of TTP therapy. Patients who do not respond to PEX and corticosteroids require additional treatments such as rituximab and caplacizumab. NAC reduces disulfide bonds in mucin polymers through its free sulfhydryl group. Thus, the size and viscosity of the mucins are reduced. VWF is structurally similar to mucin. Based on this similarity, Chen and colleagues showed that NAC can reduce the size and reactivity of ultralarge multimers of vWF, such as ADAMTS13. Currently, there is not much information to suggest that NAC has any clinical value in the treatment of TTP. In this case series of 4 refractory patients, we would like to present the responses we obtained with the addition of NAC therapy. NAC can be added to PEX and glucocorticoid therapy as supportive therapy, especially in unresponsive patients.

Refractory thrombotic thrombocytopenic purpura treated successfully with monoclonal antibody (rituximab)

Thrombotic thrombocytopenic purpura (TTP) is a nonimmune, microangiopathic hemolytic anemia, associated with thrombocytopenia, fever, neurologic, or renal dysfunction. Plasma exchange (PEX) with or without steroids constitutes first-line therapy in TTP. However, a subset of the patients may be refractory to PEX. Rituximab appears to be an alternative effective therapy for refractory or relapsing TTP. Here, we report a case of TTP in a 43-year-old female presented with fever, generalized weakness, headache, vomiting, and ecchymotic patches over forearms and upper chest for 7 days along with one episode of seizure. The laboratory evaluation revealed severe thrombocytopenia, anemia, and indirect hyperbilirubinemia with peripheral blood smear showing schistocytes (fragmented red blood cells). Initial therapy with multiple PEXs along with parenteral corticosteroids resulted in only minimal improvement of platelet count. Subsequently, rituximab was administered which helped in normalization of platelet count and overall clinical improvement. This case highlights the importance of timely utilization of second-line drugs such as rituximab in refractory TTP.

Successful Treatment with Bortezomib for Refractory Thrombotic Thrombocytopenic Purpura Associated with Systemic Lupus Erythematosus.

Thrombotic thrombocytopenic purpura (TTP) is a life- threatening disease that can be secondary to systemic lupus erythematosus (SLE). The fist- line treatments of TTP are steroid, immunosuppressor and plasm exchange (PE). However, some patients may have a poor response to these treatments. Bortezomib is a selective proteasome inhibitor and widely used to treat patients with multiple myeloma (MM). In recent years, bortezomib has been used to treat patients with refractory TTP. Here we report a patient with refractory TTP associated with SLE and had a successful treatment with bortezomib.

P.89 Management of refractory thrombotic thrombocytopenic purpura presenting in the pregnancy

P.89 Management of refractory thrombotic thrombocytopenic purpura presenting in the pregnancy

Rituximab related non-infectious lung injury complicating treatment of severe TTP in pregnancy – literature review and case-report

Background: Thrombotic thrombocytopenic purpura (TTP) in pregnancy is a rare but potentially life-threatening condition. Management of severe, refractory TTP during pregnancy is challenging and includes multidisciplinary approach. The prognosis of cases with a variety of hematological and autoimmune diseases, including TTP has changed profoundly after the rituximab therapy was introduced into clinical practice. However, adverse pregnancy outcomes associated with biological agents should be kept in mind and the decision to treat should be weighed by measurement of potential risks vs benefits. Case report: We reported the first documented case of noninfectious lung toxicity in pregnancy related to rituximab use for TTP treatment. 26 y/o patient at 23 weeks gestation initially presented to ED secondary to numbness, headache, and slurred speech with negative brain imaging. Her laboratory findings revealed severe deficiency of platelets, hemoglobin and ADAMT13 activity. She underwent multiple therapeutic interventions including plasmapheresis, intravenous immunoglobulins (IVIG), prednisone, and eventually required more often hospitalizations. Ultimately, the decision was made to proceed with rituximab therapy. After the third infusion of rituximab, she developed non-infectious lung injury without evidence of SARS-CoV-2 or other infections, pulmonary edema, or pulmonary embolism. The maternal condition worsened acutely resulting in significant desaturation that required intubation and eventual emergent premature delivery at 31-weeks’ gestation via C-section. Conclusion: Rituximab therapy for TTP management in pregnancy may be associated with significant adverse maternal-fetal outcomes. Risks and benefits of treatment should be discussed with each patient and during multidisciplinary communications. Physicians should maintain high index of suspicion for non-infectious lung injury associated with rituximab treatment in order to be able to diagnose this complication early and start treatment to avoid severe mortality and morbidity.

Multiorgan failure and ischemic cardiomyopathy with microthrombosis–induced plasmapheresis–refractory thrombotic thrombocytopenic purpura revealed by autopsy

Multiorgan failure and ischemic cardiomyopathy with microthrombosis–induced plasmapheresis–refractory thrombotic thrombocytopenic purpura revealed by autopsy

REFRACTORY THROMBOTIC THROMBOCYTOPENIC PURPURA DUE TO COVID-19

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Thrombotic Thrombocytopenic Purpura (TTP) is a hematologic emergency with a mortality of 90% if left untreated. Its is formerly characterized by a pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia (MAHA), acute kidney injury (AKI), and neurologic deficits. These were classic before the routine use of therapeutic plasma exchange (PEX) because the majority of patients developed progressive thrombotic microangiopathy(TMA) and died from untreated disease. There are multiple etiologies associated with TTP and among those rarely reported is COVID-19. SARS-CoV-2 can result in the production of platelet-rich microthrombi and decrease the level of ADAMTS13. This can precipitate TMA and rarely result in TTP. CASE PRESENTATION: A 44-year-old African-American Female with no medical history presented to our facility complaining of vomiting and diarrhea associated with bleeding gums and easy bruising. On presentation, she was calm with stable vital signs. On physical exam, she had scleral icterus and conjunctival pallor associated with petechial rash and localized ecchymosis. Initial labs were remarkable for anemia(8.6g/dL), severe thrombocytopenia(3x103/µL), AKI(creatinine 1.70mg/dL), elevated lactate-dehydrogenase(1297Units/L), and high D-dimer(636ng/mLDDU). Hemolysis workup revealed MAHA and schistocytes were confirmed on blood smear. The PCR for COVID-19 was positive. All stool studies and other workup was unremarkable. Her PLASMIC score was 6 indicating high risk for severe ADAMTS13 deficiency, and therefore she was immediately admitted to the ICU and started on steroids, rituximab, and PEX. After 5-days of PEX, her platelet count improved to 199x103/µL and was deemed responsive to initial therapy. The following day the platelet count dropped to 8x103/µL and the patient was restarted on PEX. She failed to improve despite appropriate therapy and the disease was deemed to be refractory. A multidisciplinary decision was made to initiate Caplacizumab. She completed a total of 17 PEX sessions and significant improvement in her clinical course was achieved. She was eventually discharged home in stable condition on a tapered course of steroids. DISCUSSION: When ADAMTS13 is deficient, von Willebrand factor multimers accumulate and increase platelet aggregation causing TTP. Since its activity testing has a prolonged turnaround time, the PLASMIC score is validated to identify patients at risk for severe ADAMTS13 deficiency and facilitate timely management. Our patient ADAMTS13 activity was 2.2% correlating with a severe deficiency. PEX is associated with a significant decline in mortality as it replaces the deficient ADAMTS13 and removes the inhibitory autoantibodies from the circulatory system. CONCLUSIONS: TTP is a hematologic emergency that requires prompt therapy. It's important to include COVID-19 as a potential etiology and to explore other therapeutic approaches for a refractory TTP. REFERENCE #1: Sayani, F. A., & Abrams, C. S. (2015). How I treat refractory thrombotic thrombocytopenic purpura. Blood, 125(25), 3860–3867 REFERENCE #2: Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol 2017; 4:e157. REFERENCE #3: Sweeney, J. M., Barouqa, M., Krause, G. J., Gonzalez-Lugo, J. D., Rahman, S., & Gil, M. R. (2021). Low ADAMTS13 Activity Correlates with Increased Mortality in COVID-19 Patients. TH open : companion journal to thrombosis and haemostasis, 5(1), e89–e103 DISCLOSURES: No relevant relationships by Joel Brooks, source=Web Response No relevant relationships by Ruben Cabrera, source=Web Response No relevant relationships by Jorge Cruz, source=Web Response No relevant relationships by Nathalie De paz, source=Web Response No relevant relationships by Tarig Elhakim, source=Web Response No relevant relationships by Jose Gascon, source=Web Response No relevant relationships by Daniel Gonzalez, source=Web Response No relevant relationships by Carlos Guida, source=Web Response No relevant relationships by Robert Hernandez, source=Web Response No relevant relationships by Ilde Lee, source=Web Response No relevant relationships by Daniel Zapata, source=Web Response

Sudden coma at the onset of severe refractory thrombotic thrombocytopenic purpura with successful treatment

Most patients develop coma several days after the onset of thrombotic thrombocytopenic purpura (TTP) caused by microvascular occlusion. However, aggravated coma as the first symptom of TTP has rarely been reported. Although plasma exchange (PEX) and steroids have reduced mortality, the prognosis of patients with TTP is still poor. We reported a patient with refractory TTP presenting with aggravated coma on admission. After days of successful PEX, rituximab, and glucocorticoid therapy for clinical remission, the patient regained consciousness and returned to his normal life with a good outcome. Our case highlights that TTP should be considered when coma occurs as the first symptom.

Acquired Thrombotic Thrombocytopenic Purpura and Acute Pancreatitis: Variable and Reciprocal Pathophysiologic Relationships

INTRODUCTIONAcquired thrombotic thrombocytopenic purpura (TTP) is an aggressive thrombotic microangiopathy (TMA). Central to the pathophysiology is loss of ADAMTS 13 activity, due to inhibitors in the acquired form, allowing circulating ulVWF multimers to activate platelets and produce organ damage from microvascular thromboses. Autopsy studies find frequent pancreatic involvement, but clinically evident acute pancreatitis (AP) is infrequently reported. The relationship of TTP and AP may be variable and complex, with either capable of precipitating, exacerbating or mimicking the other. More so than other organ systems, the pancreas has immense potential for cytokine production and proteolytic enzyme release. This characteristic may contribute to the reciprocal fueling, and thus severity, of TTP in association with pancreatitis.METHODSWe generated a descriptive, retrospective case series, querying the Methodist Environmental for Translational Enhancement and Outcomes Research database, a system that integrates Houston Methodist Hospital patient data into a single, comprehensive warehouse. We included all patients in whom TTP and AP were diagnosed during the same hospitalization between 2006 and 2016. Baseline demographics, laboratory values, time between onset of TTP and AP, complications, treatment, as well as short term morbidity and mortality were analyzed.RESULTSTwelve patients were identified as having TTP and AP in the same hospitalization. Demographics, onset intervals, and laboratory values of all patients are summarized in Table 1. Four patients had likely TTP induced AP with time to AP onset between 3 to 28 days, while eight patients had concurrent TTP and AP at initial presentation. All patients had elevated LDH levels with a range of 1575 U/L to 28,342 U/L and decreased platelet counts with a range of 5 k/µL to 59 k/µL. In the seven cases where ADAMTS13 measurements were performed prior to plasma exchenge (PEX), levels were below 5%. With the exception of case 5 in whom mild disseminated intravascular coagulation may have played a role in addition to TTP, no alternative etiologies were identified for the induction of the AP or the TMA.Gastrointestinal (GI) symptoms were observed in 91% of the patients, with severe cases exhibiting ischemic colitis and GI bleeds. Eighty-one percent experienced neurological symptoms, of which 80% were considered major (coma, stroke seizures, or transient focal abnormalities) and the remaining minor (transient headache or confusion). Occurring more often than in TTP patient without AP, significant renal manifestations were seen in 81% (44% progressing to renal failure requiring dialysis), and acute coronary syndromes were experienced by 50%. All patient received fresh frozen plasma, PEX, and glucocorticoids for their TTP. However, 67% of the patients had refractory TTP, of which two thirds required the addition of rituximab. With the exception of two patients who expired secondary to cardiac arrests, all others achieved normalization of their platelets by discharge. Details of the organ involvements, treatments, and complications are summarized in Table 2.CONCLUSIONWe describe twelve patients with clinically evident acute pancreatitis in association with TTP. Compared to the severely ADAMTS13 deficient (<10%) patients reported in other studies, our patients suffered significantly worse organ involvement (George, 2010). Pancreatic cytokine release observed in other studies may have contributed to ADAMTS13 depletion, contributing to the phenotypic severity (Reiter et al, 2003; Bernardo et al, 2004; Mannucci et al, 2004; Swisher et al, 2007; Morioka et al, 2008). A review of literature also revealed the role of pancreatitis in nitric oxide depletion and complement activation, which may augment micro-thrombi formation and fuel TTP propagation. Whereas the relationship between TTP and other organ systems may be one of cause and effect, the relationship between AP and TTP may be one of reciprocal fueling. As such, early appreciation and treatment of pancreatitis might significantly decrease the severity of TTP and improve patient outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Unresponsive Thrombotic Thrombocytopenic Purpura (TTP): Challenges and Solutions.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy secondary to a severely decreased A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats 13 (ADAMTS13) activity, resulting in the formation of widespread von Willebrand factor - and platelet-rich microthrombi. ADAMTS13 deficiency is mainly acquired through anti-ADAMTS13 autoantibodies in adults. With modern standards of care, unresponsive TTP has become rarer with a frequency of refractory/relapsing forms dropping from >40% to <10%. As patients with unresponsive TTP are at increased risk of mortality, prompt recognition and early therapeutic intensification are mandatory. Therapeutic options at the disposal of clinicians caring for patients with refractory TTP consist of increased ADAMTS13 supplementation, increased immunosuppression, and inhibition of von Willebrand factor adhesion to platelets. In this work, we focus on possible therapies for the management of patients with unresponsive TTP, and propose an algorithm for the management of these difficult cases.

Clinical case of CNS-involved refractory thrombotic thrombocytopenic purpura

Clinical case of CNS-involved refractory thrombotic thrombocytopenic purpura

Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N-acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.

Successful treatment of refractory thrombotic thrombocytopenic purpura with cyclosporine; a case report

Thrombotic thrombocytopenic purpura (TTP) is a rare and fetal disease of the blood coagulation system. The treatment of choice for TTP is plasma exchange. There are some different medical remedies for refractory cases with their own complications. The following case is the report of a refractory TTP, who responded to cyclosporine as a newer way of medical treatment. A 42-year-old woman with systemic lupus erythematosus (SLE) was admitted because of hypermenorrhea, hematuria and purpura. She was involved with acute renal failure, fever and seizure in the course of her admission. Fragmented RBC was detected in the peripheral blood smear. Lactate dehydrogenase (LDH) raised up to 1500 U/L. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) level was reduced and von Willebrand factor-cleaving protease (ADAMTS13) antibodies were elevated significantly. She was undergone plasma exchange in order to manage TTP. Additionally, she received methylprednisolone for the treatment of TTP. Despite initial response to plasma exchange and methylprednisolone, the patient did not improve. She received cyclosporine for the treatment of refractory TTP. Her clinical and laboratory abnormalities improved significantly with cyclosporine and this response was durable. We concluded that cyclosporine can be an effective treatment in refractory TTP and SLE.

THROMBOTIC MICROANGIOPATHY: A RARE SEQUELAE OF ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Thrombotic microangiopathy (TMA) is characterized by many etiologies, however it is not often described as a complication of Endoscopic Retrograde Cholangiopancreatography (ERCP). Failure to identify the relationship between TMA and ERCP may result in delay of diagnosis and poor patient outcomes. We present a case of a young healthy female who developed TMA after ERCP. CASE PRESENTATION: A 26-year-old woman presented to the hospital with complaints of abdominal pain, nausea and vomiting. An abdominal CT scan showed cholelithiasis and choledocholithiasis and the patient was scheduled for ERCP. She tolerated the procedure well with no immediate complications. However, a day after procedure, labs showed elevated serum lipase and amylase levels with renewed abdominal pain. Two days after ERCP she developed fever, severe thrombocytopenia, anemia and acute kidney injury (AKI) evidenced by elevated serum creatinine. A preliminary diagnosis of thrombotic thrombocytopenic purpura (TMA) was considered. Plasma exchange therapy with platelet transfusion and high dose steroids was initiated. She also received multiple packed red cell transfusion for severe anemia. ADAMTS13 antibody testing returned low at 53% with negative anti-ADAMTS13 IgG. After 7 daily sessions of plasma exchange platelets improved, AKI and anemia resolved, and the patient was discharged from the hospital. DISCUSSION: Literature review shows only about 4 cases of ERCP induced TMA. A well-known complication of ERCP is pancreatitis and a rare unfortunate sequela of this is TMA. There is a known correlation between TMA and pancreatitis, though the mechanism by which this occurs is still not well understood. Endothelial damage, cytokine release and platelet activation are thought to be the pathophysiological links between these two conditions (1). Cytokines cause release of ultra-large von-Willebrand factor (VWf) molecules that attach to activated platelets promoting aggregation, clumping and thrombus formation. There is concomitant reduction in serum ADAMTS13, which would normally cleave the ultra-large VWf, due to pancreatic enzyme degradation. CONCLUSIONS: This case illustrates how complicated the diagnosis of TMA can be, but also points out how clinical judgment is imperative to prompt early treatment and increase favorable outcomes. TMA caused by ERCP is rare, but recognizing this link is important for immediate initiation of life saving treatment. Reference #1: 1. Malik, F., Ali, N., Ahsan, I., Ghani, A. R., & Fidler, C. (2016). Eculizumab refractory thrombotic thrombocytopenic purpura secondary to post-endoscopic retrograde cholangiopancreatography pancreatitis in a patient. Journal of community hospital internal medicine perspectives, 6(6), 32310. DISCLOSURES: No relevant relationships by Kitson Deane, source=Web Response No relevant relationships by Abidemi Idowu, source=Web Response

Caplacizumab: First Case of Thrombotic Thrombocytopenic Purpura Refractory Treated in Spain outside Clinical Trial

Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy, caused by a deficiency of ADAMTS-13 (a desintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). It is considered a medical emergency and its standard treatment is based on plasma exchange associated with high doses of corticosteroids. Those patients refractory to standard treatment have a high risk of morbidity-mortality. Through this clinical case, a patient refractory to all the treatments is presented. She was treated whit caplacizumab that is humanized bivalent antibody acting against the domain A1 of the von Willebrand factor and prevents interaction with the glycoprotein Ib-IX-V (GPIb-IX-X). After one year from the end of treatment, the patient remains stable and asymptomatic. Caplacizumab is a good choice in those patients who do not respond to any of the standard treatments and that can lead to a decrease in mortality in patients with refractory thrombotic thrombocytopenic purpura.

Diagnosis and treatment of thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease in which platelets are consumed and thrombotic microangiopathy develops in multiple organs due to a severe deficiency of the metalloproteinase, ADAMTS13. TTP should be suspected in any case associated with thrombocytopenia and hemolytic anemia; TTP can be diagnosed in cases of profound reduction in ADAMTS13 activity (to <10% of the normal level). Congenital TTP involves mutations in the ADAMTS13 gene, whereas acquired or autoimmune TTP results from the actions of inhibitory autoantibodies against the ADAMTS13 protein. Plasma exchange together with corticosteroids is an effective treatment for acquired TTP; plasma exchange removes autoantibodies and provides ADAMTS13 supplementation, whereas corticosteroids further suppress autoantibody generation. Rituximab was recently approved in Japan for use in refractory or relapsing TTP. Likewise, caplacizumab, an anti-von Willebrand factor, may contribute to disease control and overall survival by preventing ongoing thrombosis and acute end-organ damage.

Consolidation with Carfilzomib, Lenalidomide and Dexamethasone (KRd) Following ASCT Results in High Rates of Minimal Residual Disease Negativity and Improves Bone Metabolism, in the Absence of Bisphosphonates, Among Newly Diagnosed Patients with Multiple Myeloma

Consolidation therapy post autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) seems to deepen disease responses. MRD negativity represents a strong prognostic factor for prolonged remission. Carfilzomib is a second-generation proteasome inhibitor, which in combination with lenalidomide has been associated with high rates of deep responses before ASCT in phase 2 studies. In this context, we prospectively evaluated the role of carfilzomib, lenalidomide and dexamethasone (KRd) as consolidation therapy post-ASCT in newly diagnosed MM pts who have not achieved MRD negative complete remission (CR). The primary endpoint was to assess KRd efficacy in terms of improving disease response, whereas secondary endpoints included percentage of minimal residual disease (MRD) (performed by Next Generation Flow Cytometry) negativity post KRd, safety, time to progression (TTP), time to next treatment (TtNT), overall survival (OS) and the effects of KRd on bone metabolism in the absence of bisphosphonate administration. All pts achieving at least partial response and less than MRD negativity post-ASCT were eligible for inclusion in the study. Consolidation consisted of 4 cycles of KRd, starting on day 100 post-ASCT: carfilzomib was given at a dose of 20 mg/m2 iv on day 1 cycle 1 and 56 mg/m2, on days 1, 8, 15 thereafter; lenalidomide was given at 25 mg daily on days 1-21 and dexamethasone at 40mg weekly every 28-days. All pts continued lenalidomide maintenance 10 mg following consolidation until progressive disease. Pts did not receive bisphosphonates during or post-ASCT as well as throughout the period of KRd consolidation. Bone remodeling was evaluated by the following serum indices before and after KRd (2 measurements for each pt): i) osteoclast regulators (soluble receptor activator of nuclear factor kappaB ligand and osteoprotegerin), ii) osteoblast inhibitors (dickkopf-1 and sclerostin) iii) bone resorption markers (CTX and TRACP-5b) and iv) bone formation markers (bone-specific alkaline phosphatase and osteocalcin). Between January 2018 and May 2019, 39 consecutive pts all MRD positive (20M/19F, median age 56 years, range 44-67 years) entered the study. The distribution per revised ISS was 36.1% stage 1, 52.8% stage 2 and 11.1% respectively. After a median follow-up of 16 months (range 1-17) following KRd initiation, 35 (89.7%) pts had received 4 cycles of KRD, whereas two pts continue on treatment and two discontinued treatment due to toxicity. Following ASCT, one (2.6%) pt had achieved stringent CR (sCR), 4 (10.3%) were in CR, 29 (74.4%) were in very good partial remission (VGPR) and 5 pts (12.8%) were in PR. Post KRd consolidation, 30 out of 37 evaluable pts (81%) pts improved their response status with KRd. Overall, 28 (75.7%) pts achieved a sCR, one (2.7%) CR and 8 (21.6%) VGPR, while 25 (67.6%) pts achieved MRD negativity at 10-5. Among the 25 MRD negative pts, 11 (44%) were R-ISS stage 1, 13 (52%) stage 2 and one (4%) stage 3. Positron emission tomography-computed tomography (PET/CT) scans that were performed in 14 MRD (-) pts were negative for all pts except one. The markers of bone metabolism were measured in 22 pts. Only TRACP-5b levels showed a significant reduction (p=0.011) post KRd consolidation, which suggests a beneficial effect on bone resorption that must be further investigated. No new skeletal-related events (SREs) were reported. No patient has progressed whereas 37/39 (95%) are alive. One patient died due to staphylococcal pneumonia and another due to refractory thrombotic thrombocytopenic purpura complicated by brain hemorrhage and in-hospital infection during KRD. 7 (18%) pts experienced ≥grade 3 toxicities (mainly infections, TTP, fatigue, neutropenia, pneumonitis, hypocalcemia and increase of γGT and ALP). There were no new cases of peripheral neuropathy. In conclusion, KRd consolidation with weekly carfilzomib, post ASCT, is highly effective and improves the quality of response by increasing MRD negativity rates. Although it is given for four cycles only, KRD consolidation reduces bone resorption and correlates with no SREs in the absence of bisphosphonates. Infections prophylaxis is strongly encouraged. This triplet combination should be further investigated as a potential consolidation regimen both for standard and high-risk pts. Disclosures Gavriatopoulou: Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses. Terpos:Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Medison: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding.