Neratinib induced diarrhea

 Prophylaxis:

Current diarrhea prophylaxis recommendations are 4 mg with the first dose of neratinib, then 4 mg 3 times on day 1 (for a total of 16 mg on day 1), 4 mg 3-times daily (for a total of 12 mg/day) on days 2 and 3, reducing to 2 mg 3- or 4-times daily (for a total of 6-8 mg/day) for the remainder of the first cycle. Nonpharmacologic interventions, including dietetic changes and increased fluid intake, are recommended for new-onset uncomplicated diarrhea.

1. Activated charcoal62 and oral alkalinization63 may be beneficial for irinotecan-associated diarrhea

2. Probiotics may have a role in preventing 5-fluorouracil (5-FU)-related diarrhea. However, studies of prophylactic octreotide and an intestinal adsorbent did not show benefit.

Reference:

Neratinib diarrhea

BCCA guideline diarrhea general

ESMO guidelines

Burkitt's lymphoma- review

 Reference:

Blood Journal Feb 2021

Burkitt's is a highly aggressive B cell lymphoma.

Key points:

1. Sporadic, endemic, immunodeficiency associated.

2. Molecular feature is translocation and dysregulation of proto-oncogene- c-myc. t(2:8) or t(8:22) with heavy chain on chr 2 or light chain on chr 22 with c-myc gene on chromosome 8.

3. Endemic Burkitt's--> equatorial Africa, chronic B cell stimulation due to EBV. bm not involved but extranodal involvement of GI tract, adrenals, kidneys, and gonads, is common

4. Sporadic is more common in the western world. CNS and bm involvement common. Leptomeningeal rather than parenchymal is common.

5. HIV-associated Burkitt's is seen in patients with preserved CD4 counts, so ART has not changed the incidence. Nodal involvement is typical, but can also have CNS, GI, and bm involvement.

6. TLS is a medical emergency and can be seen even before treatment starts ie. spontaneous TLS.

evidence of spontaneous TLS or those at high risk, defined as stage III/IV disease and/or LDH ≥2 times the upper limit of normal, consensus guidelines recommend the use of rasburicase

Copyright ASH 2021

Treatment:

1. Low risk- single lesion < 10 cm, or resected abdominal disease and normal LDH-CODOX-M 3 cycles

The CODOX-M regimen is as follows:

• Cyclophosphamide 800mg/m² IV on day 1, followed by 200 mg/m² IV on days 2-5

• Doxorubicin 40 mg/m² IV on day 1

• Vincristine 1.5 mg/m² IV (no capping of dose) on days 1 and 8 (cycle 1), as well as on days 1, 8, and 15 (cycle 3)

• Methotrexate 1200 mg/m² IV over 1 hour on day 10; then 240 mg/m²/h for the next 23 hours; leucovorin rescue begins 36 hours from the start of the methotrexate infusion

• Intrathecal cytarabine 70 mg (patient older than age 3 y) on days 1 and 3

• Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 15

2. All other patients i.e. high risk-CODOX-M alternating with IVAC for 2 cycles. Add Rituxan to this regimen if using.

The IVAC regimen is as follows:

• Ifosfamide 1500 mg/m² IV on days 1-5, with mesna protection

• Etoposide 60 mg/m² IV on days 1-5

• Cytarabine 2 g/m² IV every 12 hours on days 1-2

• Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 5

Administration of colony-stimulating factors is usually started 24 hours after completion of chemotherapy and continues until the ANC >1000/μL.

Preferred regimen- DA-R-EPOCH

Patients were treated with 2 cycles beyond complete remission (6 to 8 total) with the exception of HIV patients who received 1 cycle beyond complete response (3 to 6 total) with 2 doses of rituximab administered with each cycle. CNS-directed therapy consisted of 8 doses of prophylactic intrathecal methotrexate with additional doses for patients with leptomeningeal disease. With long-term follow-up of >6 years, freedom from progression and OS were 95% and 100%, respectively.

Anthracycline free regimen in early TNBC?

 56 yo postmenopausal F with no family hx, positive for BRCA 1, presents with R breast self palpated lump 2.3 cm, 1 LN in R axilla biopsy-proven.

You discuss neoadjuvant treatment with her.

a. What is the current standard of care?

b. What do you tell her about prognosis?

c. What new data has come out in the last few years that may indicate a future direction?

Answers:

a. Current SOC is an anthracycline-based NACT. The goal is to achieve path CR. For those who do not achieve path CR, adjuvant capecitabine based on CREATE-X is recommended.

Using data from KEYNOTE 522 data NEJM which I will discuss later, the path CR in the SOC arm which included anthracyclines was 51.2%. Very high grade 3 toxicity in both arms, approximately 73%.

Path CR in the pembro arm was 65% with grade 3 or higher of 78%. Remember this arm also got anthracycline.

The question now is can we avoid anthracycline altogether?

2 papers:

NEOSTOP trial showed path CR rates of 54% in anthracycline arm+ platinum and taxol ( standard 12 weeks platinum taxol then 4 cycles DDAC) and platinum taxotere alone for 6 cycles.

At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in anthracycline arm compared with anthracycline free, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. 

Below are the results of a meta-analysis that further supports this notion of anthracycline free chemotherapy regimens.

Meta-analysis JCO

"For TNBC, adding Pl or B into the neoadjuvant therapy regimen brings about a higher pCR rate, though they are associated with an increase in hematologic or gastrointestinal complications. The benefit of adding anthracyclines to the neoadjuvant chemotherapy regimen for TNBC is not apparent"

Based on this, my suspicion is that we will be moving to 12-16 weeks of carboplatin-taxane and keytruda followed by Keytruda maintenance if this can be proven in a phase III RCT.

Prognosis of patients who get NACT with or without path CR- refer to CREATE X trial results

What about low dose Xeloda maintenance?

Ans: applies to those who got adjuvant rather than NACT

PARP and prostate cancer

PROFOUND study

Reference NEJM: Olaparib mCRPC

Germline and somatic BRCA mutation, progressed on hormonal agent like abi or enza

Longer PFS by 3 months in PARP group( 7.4 versus 3.6 months)

Anemia is the most common AE. No AML or MDS reported.

Nausea also common

Key points

1. ATM mutations do not respond to PARP inhibitors
2. Can use PARP inhibitor even with monoallelic BRCA mutation
3. DO not sequence another PARP after failure of one PARP
4. Do germline testing in all metastatic prostate cancer patients. Somatic testing is also recommended.

TTP-aHUS

 Causes of thrombotic microangiopathies beyond TTP and HUS

1. Sepsis
2. DIC
3. Malignant hypertension
4. Pregnancy
5. Drug induced
6. Cancer associated
7. Hematopoietic Stem cell transplant TMA
8. Cobalamin C defect
9. DGKE deficiency

Reference: ASH education TTP HUS and beyond

Approach- pearls

1. In a patient who responds poorly to PEX with no other clear explanation for the TMA findings, a diagnosis of aHUS might then become more plausible on the differential diagnosis as an explanation for the TMA.

2. In many of these disorders, the ADAMTS13 activity will be below “normal” or even very low (10%-20%) but not severely deficient (<10%), which typically characterizes acquired TTP

Let us look at the uncommon ones first:

a. DGKE deficiency presents in the first year of life and PEX does not work.

b. Cobalamin C defect: Extremely rare but important to identify.

Patients present with pulmonary artery hypertension, kidney failure, hyperhomocysteinemia, decreased methionine, and normal vitamin B₁₂ levels. Recovery is typically complete after starting treatment, which includes high-dose hydroxycobalamin, betaine, and folinic acid.

c. Hematopoietic stem cell transplant-associated TMA--> TA-TMA

TA-TMA commonly affects the kidneys and results in transfusion-dependent anemia and thrombocytopenia; however, it can also present with multisystem organ injury that includes: pulmonary hypertension, intestinal TMA, posterior reversible encephalopathy syndrome (secondary to uncontrolled hypertension), and polyserositis. Proteinuria and elevated LDH.

Trigger for complement activation ( could be a board question)-copy number variants in genes CFHR3-CFHR1 and acquired complement dysregulation through the formation of neutralizing autoantibodies to Factor H.

Treatment: Eculizumab, supportive care, discontinue calcineurin inhibitors

PEX not very effective <50%

d. Atypical HUS: Complement mediated disorder due to  either

-loss of function mutations in factor H ( board question)

-gain-of-function mutations in factor B or C3 that are potentially pathologic in aHUS

e. TMA in cancer: chemo induced, or bm involvement. Gastric, breast and mucinous adenoca at highest risk.

Compared with patients with acquired TTP, patients with cancer-associated TMA may have new or exacerbated hypertension, greater pulmonary involvement (dyspnea, cough, abnormal chest radiograph), or a leukoerythroblastic reaction on peripheral smear

Rx: treat cancer, no role for PEX, stop any offending drugs.

Common drugs in cancer associated with TMA: different immunotoxins, immunotherapy, anti-VEGF therapy (appears to be a class effect), and imatinib

f. Drug induced TMA- commonest drug is quinine. Ask for OTC anticramp tonics.

2 mechanisms- immune mediated and direct endothelial injury.

Quinine induces TMA by immune mechanism.

Direct toxicity- sirolimus and tacrolimus reduce VEGF on endothelial cells

Rare case report of bortezomib and carfilzomib induced TMA. 

Diagnosis: can be made by drug dependent antibodies

 The most common drugs associated with immune-mediated DI-TMA are quinine, oxaliplatin, and quetiapine, 

Direct toxic mechanism are cyclosporine, tacrolimus, sirolumus, bevacizumab, interferons α and β, and mitomycin. 

Gemcitabine is the only medication that has been associated with both immune-mediated³⁷  and toxic mechanisms.  Illicit drugs, specifically cocaine and IV use of oxymorphone (OPANA ER), have also been reported to cause a DI-TMA

Treatment:

1. Avoid the drug, renal recovery is the slowest, CBC improves faster

2. With immune toxicity, never rechallenge, with direct toxicity ok to rechallenge

3. PEX no use

4. Can consider eculizumab for gemcitabine TMA

HELLP syndrome- treatment --> delivery of baby, control BP

Atypical HUS is common post partum; 1/3 of HELLP can be post partum, otherwise mostly in weeks 28-36.

ddx fatty liver of pregnancy-- often indistinguishable from  HELLP. the only diagnosis to rule out is infectious hepatitis and if this is negative, plan to deliver the baby and maximize supportive care.

Clinical pearl--> in acute fatty liver of pregnancy-DO NOT do a liver bx

Liver biopsy should not be performed to confirm a diagnosis of AFLP or to distinguish AFLP from severe pre-eclampsia, because management of both conditions are the same. 

ASH education 2020 Transfusion in MDS

 RBC transfusion in MDS

1. The ideal threshold for Hb transfusion is not known. In patients, typically younger patients undergoing hematopoietic stem cell transplantation, a restrictive threshold of 7gm was considered safe.

2. Reactions- minor febrile reactions, TACO. Whether transfusing fewer units at a time, or more slowly, or accompanied by prophylactic diuretics reduces TACO risk for patients with MDS is not known.

3. Alloimmunization can be a problem upwards of 25%. antibodies to K and the Rh system antigens (especially anti-E) are the most common; therefore, providing RBCs negative for these antigens may be sufficient to minimize alloimmunization for most patients.

4. Iron overload is another problem both due to ineffective.

5. Iron chelation- can reduce transfusion requirements and should be considered early for patients who become transfusion dependent. However, determining who is a candidate for chelation can be difficult; higher-risk patients needing greater transfusion intensity will become iron loaded more quickly but may not benefit from chelation because of their shorter survival.